Reseptorityyppinen proteiinityrosiinifosfataasi zeta , PTPRZ1

 https://www.ncbi.nlm.nih.gov/protein/NP_001193768.1

http://www.jcancer.org/v10p1663.htm
Available studies demonstrate that receptor-type tyrosine-protein phosphatase zeta (PTPRZ1) is expressed in different tumor tissues, and functions in cell proliferation, cell adhesion and migration, epithelial-to-mesenchymal transition (EMT), cancer stem cells and treatment resistance by interacting with or binding to several molecules.
 These included pleiotrophin (PTN), midkine, interleukin-34, β-catenin, VEGF, NF-κB, HIF-2, PSD-95, MAGI-3, contactin and ErbB4.
 PTPRZ1 was involved in survival signaling and could predict the prognosis of several tumors. This review discusses: the current knowledge about PTPRZ1, its expression, co-receptors, ligands, functions, signaling pathway, prognostic values and therapeutic agents that target PTPRZ1.
Keywords: PTPRZ1, pleiotrophin, midkine, review

PTPRZ1 gene encodes receptor-type tyrosine-protein phosphatase zeta (PTPRZ1), which is expressed in different cancer tissues as either a chondroitin sulfate (CS) proteoglycan or a nonproteoglycan form [1, 2]. PTPRZ1 is overexpressed in several tumors, such as lung cancer, cervical cancer, hepatocarcinoma, renal cancer, and glioblastoma [3-7]. PTPRZ1 is localized not only in its normal association with the cell membrane but also scattered in cytoplasm and in nuclei in different breast cancer cells and, in the case of infiltrating ductal carcinomas, the distribution of PTPRZ1 changes as the breast cancer become more malignant[8]. PTPRZ1 has different functions in the cancer development, progression and metastasis, further influences the cancer treatment and prognosis. In order to comprehensively review the recent research on PTPRZ1 gene and PTPRZ1, we reviewed the relevant studies based on medical databases and analyzed its expression, prognostic values based on TCGA data.

Pubmed and EMBASE was comprehensively searched using “PTPZ” or “PTPRZ” or “RPTPB” or “PTP18” or “phosphacan” or “HPTPZ” or “RPTPbeta” or “HPTPzeta” or “R-PTP-zeta-2” or “PTP-ZETA” or “protein tyrosine phosphatase, receptor type Z1” or “RTP Type Z1” or “receptor-type tyrosine-protein phosphatase zeta” or “Protein-tyrosine phosphatase receptor type Z polypeptide 1” or “Protein-tyrosine phosphatase receptor type Z polypeptide 2”. There were no language, publication date, or publication types restrictions. The search was conducted at February 12, 2018, and updated at September 1, 2018. 345 citations from Pubmed and 356 citations from EMBASE were retrieved. TCGA (The Cancer Genome Atlas, https://cancergenome.nih.gov/) data was reviewed to analyze the expression of PTPRZ1 gene and PTPRZ1 gene mutations. The prognostic values of PTPTZ1 gene in different kinds of cancer were analyzed using GEPIA (http://gepia.cancer-pku.cn/) [9]. The protein-protein interaction (PPI) networks from available studies and public databases were conducted and visualized by the Cytoscape software.

Gene expression and mutations

The expression of PTPRZ1 gene, gene mutations, gene fusions were analyzed based on TCGA databases.
Patients with glioblastoma multiforme (GBM) expressed the highest PTPRZ1 gene level, followed by brain lower grade glioma (LGG) and head and neck squamous cell carcinoma (Figure 1).
 PTPRZ1 was up-regulated in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), GBM, LGG, lung squamous cell carcinoma (LUSC),
and down-regulated in breast invasive carcinoma (BRCA), colon adenocarcinoma (COAD), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), and stomach adenocarcinoma (STAD). The rates of PTPRZ1 gene mutations were different across tumors, and uterine corpus endometrial carcinoma (UCEC) (16.79%) has the highest rate of PTPRZ1 gene mutation, followed by lung adenocarcinoma (LUAD) (12.87%) and skin cutaneous melanoma (SKCM) (12.15%) (Figure 2).
Fusion genes combine parts of two or more original genes, generating from chromosomal rearrangement or abnormal transcription. About 25 PTPRZ1 fusion genes were found[10] (Table 1), but few of them were well studied.
PTPRZ1-MET fusion was found in 7.7% grade III astrocytomas (1/13) and 15.0% secondary glioblastomas (3/20), and tumors from patients harbouring PTPRZ1-MET-fused glioblastoma are resistant to temozolomide therapy and have significantly compromised overall survival rates [11, 12]. PTPRZ1-MET exosomes exhibit a more aggressive phenotype and induce epithelial-to-mesenchymal transition (EMT), enhance tumorigenicity and angiogenesis, promote cell migration and invasion, promote neurosphere formation and angiogenesis [11]. PTPRZ1-MET induces gliomas through elevated expression levels of MET mRNA, preserve fundamental properties of wild-type MET, and enhance phosphorylation [13].  
PTPRZ1-NFAM1 fusion could be harbored in spitzoid melanoma[14]. This fusion was associated with elevated expression of the NFAT activated protein with ITAM motif 1 (NFAM1), and the protein encoded by NFAM1 contains an immune-receptor tyrosine-based activation motif that is thought to regulate the development of B cells[15].

 Table 1  PTPRZ1-fusion genes

Band 1	Band 2	Fusion	Partner 1	Partner 2	cancer
7q31	2q21	ARHGEF4/PTPRZ1	PTPRZ1	ARHGEF4
7q31	7q11	CLIP2/PTPRZ1	PTPRZ1	CLIP2	Brain Lower Grade Glioma
7q31	3p21	CSPG5/PTPRZ1	PTPRZ1	CSPG5	Brain Lower Grade Glioma
7q31	1q42	GALNT2/PTPRZ1	PTPRZ1	GALNT2	Skin Cutaneous Melanoma
7q31	Xp11	HUWE1/PTPRZ1	PTPRZ1	HUWE1	Brain Lower Grade Glioma
7q31	7q22	KMT2E/PTPRZ1	PTPRZ1	KMT2E	Stomach Adenocarcinoma
7q22	7q31	MLL5/PTPRZ1	MLL5	PTPRZ1	Stomach Adenocarcinoma
7q31	16q21	PTPRZ1/ADGRG1	PTPRZ1	ADGRG1	Brain Lower Grade Glioma
7q31	1q22	PTPRZ1/CCT3	PTPRZ1	CCT3	Brain Lower Grade Glioma
7q31	7q31	PTPRZ1/DOCK4	PTPRZ1	DOCK4	Malignant melanoma
7q31	17p11	PTPRZ1/EPN2	PTPRZ1	EPN2	Brain Lower Grade Glioma
6q21	7q31	PTPRZ1/FYN	PTPRZ1	FYN	Brain Lower Grade Glioma, Glioblastoma Multiforme
7q31	17q21	PTPRZ1/GFAP	PTPRZ1	GFAP	Glioblastoma Multiforme
7q31	1q25	PTPRZ1/HMCN1	PTPRZ1	HMCN1
7q31	7q31	PTPRZ1/MDFIC	PTPRZ1	MDFIC	Stomach Adenocarcinoma
7q31	7q31	PTPRZ1/MET	PTPRZ1	MET	Glioblastoma Multiforme, Brain Astrocytoma, grade I-II
7q31	22q13	PTPRZ1/NFAM1	PTPRZ1	NFAM1	Lung, Heart, Skin, Melanocytic neoplasm
7q31	19p13	PTPRZ1/PIN1	PTPRZ1	PIN1
7q31	7q31	PTPRZ1/PTPRZ1	PTPRZ1	PTPRZ1
7q31	19p13	PTPRZ1/SMARCA4	PTPRZ1	SMARCA4	Brain Lower Grade Glioma
7q31	7q32	PTPRZ1/SND1	PTPRZ1	SND1
7q31	7q11	PTPRZ1/SRRM3	PTPRZ1	SRRM3	Malignant melanoma
7q31	7q32	PTPRZ1/TSPAN33	PTPRZ1	TSPAN33	Head and Neck Squamous Cell Carcinoma, Oral cavity Squamous cell carcinoma
7q31	7q32	PTPRZ1/UBE2H	PTPRZ1	UBE2H	Breast Adenocarcinoma
7q31	7q31	ST7/PTPRZ1	ST7	PTPRZ1	Prostate Adenocarcinoma
7q31	19p12	ZNF708/PTPRZ1	PTPRZ1	ZNF708 https://www.ncbi.nlm.nih.gov/protein/NP_067092.2

 Figure 1   ..

The structure and ligands of PTPRZ1

Several splice variants of PTPRZ1 have been discovered, including PTPRZ1-A (9.4 kb), a full-length transmembrane receptor form; PTPRZ1-B (6.4 kb), a short transmembrane receptor form with a deletion in the extracellular region; the other two are soluble secreted forms that lack both a transmembrane region and tyrosine phosphatase activity (phosphacan, short (4 kb) and long (8.4 kb; also known as phosphacan, PTPRZ-S)) [1, 2, 6, 16-18]. PTPRZ1-A and PTPRZ1-B are composed of several modular structural domains, including an N-terminal carbonic anhydrase-(CAH) like domain, a fibronectin type III domain, a serine, glycine-rich domain for chondroitin- sulfate (CS) attachment, a transmembrane segment, and two protein tyrosine phosphatase (PTP) domains plus C-terminal PDZ-binding motif [1, 16].
The membrane proximal phosphatase domain (D1) is active, but the distal D2 domain is inactive[19]. A novel PTPRZ1 receptor sub-isoforms without a seven-amino acid sequence encoded by exon 16 was identified, which forms a part of the helix-turn-helix segment called the 'wedge' structure and is located at the N-terminal region in the membrane-proximal protein tyrosine phosphatase domain[20].
The extracellular region of PTPRZ1 binds to several cell molecules, including various secretory factors (pleiotrophin (PTN), midkine (MK), interleukin-34 (IL-34)), extracellular matrix proteins (tenascin- C and tenascin-R), and neuronal cell adhesion molecules (NrCAM, L1/Ng-CAM, F3/contactin, neural cell adhesion molecule, contactin-1 and contactin-2/ TAG-1/axonin-1) as well as amphoterin and fibroblast growth factor-2 (FGF-2). [3, 5, 6, 21-24].

PTN

PTN, IL-34 and midkine (MK) interact with the glycosaminoglycan structures of PTPRZ1, have been shown to function as inhibitory ligands against the tyrosine phoshatase activity of PTPRZ1 [21, 22]. PTN is the most potent known natural ligand of PTPRZ1 and strongly inhibits its activity putatively through ligand-induced dimerization of the active D1 domain of PTPRZ1[25]. The C-terminal tail of PTN is essential for maintaining stable interactions with chondroitin sulfate (CS) A, the type of CS commonly on PTPRZ1, which explained why truncated PTN missing the C-terminal tail is unable to signal through PTPRZ1 [26]. PTN-mediated PTPRZ1 oligomerization, which might inhibit PTPRZ1's phosphatase activity may involve both core protein and glycan components of PTPRZ1 [27]. PTPRZ1 signals through 'ligand-dependent receptor inactivation' of PTN and disrupts its normal role in the regulation of tyrosine phosphorylation of downstream signalling molecules [6, 28]. PTPRZ1-PTN interaction results in accumulation of tyrosine phosphorylation of multiple downstream proteins including SRC kinase, calmodulin, anaplastic lymphoma kinase (ALK), GIT1/Cat1, β-catenin, β-adducin, Fyn, GIT1/Cat-1, and P190RhoGAP, which in turn have been related to activation of multiple pro-tumorigenic signaling cascades[4, 6, 8, 28, 29]. PTPRZ1-PTN interaction modulates the tyrosine phosphorylation of factors that control cell-matrix interactions, cell-cell adhesion, cell migration, tumor cell invasion, tumor growth and metastasis [2, 4, 5, 29-32].
PTPRZ1, syndecan-3 (N-syndecan, SDC3), and ALK have been characterized as PTN transmembrane receptors and to be implicated in its signaling [31-34]. PTN activates its cell surface receptors, regulating multiple functions including cell adhesion, cell migration, cell proliferation and cytoskeletal stability and negatively regulated PTPRZ1[35]. A more recent study isolated and characterized two forms of PTN, a full-length form (PTN18) which induced haptotactic migration, whereas the shorter (PTN15) activated a mitogenic signal transduction pathway. PTN15 stimulation through ALK activates a mitogenic signal transduction pathway, whereas binding of immobilized PTN18 to PTPRZ1 induces cell migration[32]. PTN has been shown to activate both the mitogen- activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3K)-Akt signaling axes, and inhibitors of Erk1/2 or PI3K inhibit DNA synthesis stimulated by PTN [34].

IL-34

PTPRZ1, was an additional IL-34 receptor [3]. IL-34 is a 241 amino acid protein, which exists in two isoforms, differing by the addition of a glutamine inserted between position 80 and 81 in the 241 aa isoform, and generated by alternative splicing. IL-34 is formed by four α-helix and disulfdes bonds that lead to the formation of a homodimeric protein. IL-34 is a cytokine relatively conserved between species with 99.6% homology between human and chimpanzee. IL-34 selectively interacts with PTPRZ1 in membrane lysates through low affinity interactions with chondroitin sulphate chains, which suppresses their tumorigenic properties in a PTPRZ1 dependent manner[24]. Studies have identified roles for IL-34 in areas as remote as neuronal protection, bone-degenerative diseases, delayedtype hypersensitivity, infection, cancer, and more recently transplantation [36]. IL-34 binds specifically to PTPRZ1 to initiate downstream signaling, further inhibits cell proliferation, clonogenicity, and motility[24].

Midkine (MK)

The C-terminally located C-domain of MK, a 13-kDa heparin-binding growth factor with 45% sequence identity to PTN, exhibited full activity for PTPRZ1 binding[37]. PTPRZ1 was involved in the haptotactic migration of UMR106 cells induced by midkine, which is highly related to PTN and binds to PTPRZ1 with high affinity [23]. MK enhances cell survival, cell migration, cytokine expression, cell differentiation, and involves in several physiological processes, including cancer, inflammation/immunity, blood pressure, development and tissue protection [38, 39].

β-catenin

β-catenin is of major importance in cell-cell adhesion, cytoskeletal structure, and signaling pathways in normal and transformed cell growth[40]. The interaction of PTPRZ1 and PTN increases the steady-state tyrosine dephosphorylation of β-catenin, which interacts with the catalytically active D1 domain of PTPRZ1[25, 28, 40-42]. This process influences the cytosolic and nuclear availability of β-catenin, and activated the β-catenin pathway [42]. In the nucleus, β-catenin displaces the transcriptional repressor Groucho/TLE by binding to TCF3 (TCF7L1) and TCF4 (TCF7L2), thereby initiating transcription [25]. PTPRZ1 increases the expression of β-catenin in the nuclear fractions and further increases the activation by β-catenin of T cell factor (TCF)- dependent transcription [25]. Mcclain et al. found PTPRZ1 inhibition also potentiated GSK3β-regulated β-catenin translocation and two pools of β-catenin, which are regulated by PTPRZ1 and GSK3β are partially but incompletely overlapping, with GSK3β appearing to regulate β-catenin availability beyond that influenced by PTPRZ1 [25]. PTPRZ1 also regulates proliferation, tumorigenesis and E-cadherin-mediated cell-cell adhesion by activating or dephosphorylating β-catenin and its downstream genes, such as cyclin D1, c-myc, c-jun, fra-1, and CD44 [7, 35, 41, 42].

MAGI, ERBB4 and PSD95

The interaction between PTPRZ1 and MAGI-1/ 3, PSD95 was found to be mediated primarily via the PDZ domain in vivo [23, 43]. The third PDZ domain of MAGI-1 is responsible for interaction with the carboxyl terminal PDZ-binding motif of PTPRZ1 [1]. Simultaneous binding of MAGI to PTPRZ1 and ERBB4 forms a complex. MAGIs can bring ERBB4 tyrosine kinase and PTPRZ1 tyrosine phosphatase to domains in the cell membrane, modulating the balance among signaling pathways downstream of these molecules [16]. An intracellular carboxyl-terminal region of PTPRZ1 pulled-down PSD95 and ERBB4 and the tyrosine phosphorylation level of ERBB4 was increased in PTPRZ1 gene deficient mice. Phosphorylation of ERBB4 was raised by PSD95, which was repressed by additional PTPRZ1 expression [44].

Others

One HIF-2-specific gene was PTPRZ1 gene, which was upregulated about six-fold by HIF-2α[45]. HIF-1α and HIF-2α can bind to hypoxia-responsive elements 4 (HRE4) of the PTPRZ1 gene promoter, and the HIF-2-specificity of PTPRZ1 is mediated at least in part by cooperative binding of HIF-2 and ELK1 to nearby sites in the PTPRZ1 gene promoter [7]. PTPRZ1-D1902A and Git1 form a stable complex in mammalian cells, Git1 bound to PTPRZ1-D1902A dependent on the tyrosine-phosphorylated Git1, which was dephosphorylated by PTPRZ1 [23]. Endogenous VEGF formed complexes with PTPRZ1, which suggested PTPRZ1 was a cell membrane binding molecule for VEGF165 [46]. Chromatin immunoprecipitation assay identified the direct binding of NF-κB to the PTPRZ1 gene promoter, and clofibrate abolished this binding[47]. The CAH domain of PTPRZ1 has been shown to bind specifically to contactin [6]. Contactin is a 140 kDa glycosylphosphatidylinositol (GPI) membraneanchored neuronal cell recognition protein. Binding of glial PTPRZ1 to the contactin/Nr-CAM complex is important for neurite growth and neuronal differentiation[6, 48]. Rokavec et al. found PTPRZ1 gene promoter contain conserved putative ZEB1- binding sites and ZEB1 bound to PTPRZ1 gene promoters in MCF-10a-T cells [49]. PTPRZ1 directly interacts with integrin α_vβ₃ on the cell surface, and integrin α_vβ₃ interacted with both the long (380 kDa) and short (220 kDa) transmembrane isoforms of PTPRZ1, as well as with a transmembrane isoform of lower molecular mass (80-90 kDa). The longer PTPRZ1 isoforms interacted specifically with α_v, while the 80-kDa band interacted specifically with the β₃ subunit[50]. PTPRZ1 provides VacA-binding sites at least in part in the gastric epithelium and binding analysis indicated that VacA directly binds to PTPRZ1-B[51]. PTPRZ1 also binds to FGF-2, NCAMs, tenascin amphoterin and tenascin-C [5, 30]. And some other relevant molecules were identified using data from Cytoscape_3.6.0 (figure 3).

The functions of PTPRZ1

Tumor cell proliferation and tumor growth

PTPRZ1 seems to be important for maximum tumor growth in situations of contact independence or in complex cellular environments, and blocking the PTPRZ1-PTN signaling potently suppressed glioblastoma growth and prolonged animal survival. PTN dephosphorylates the constitutively active PTPRZ1, which upon binding PTN dimerizes and becomes inactivated, resulting in an increase in tyrosine- phosphorylated β-catenin[28]. It further leads to increased levels of cytoplasmic β-catenin which translocates to the nucleus where it binds to the transcription factor TCF/LEF; this causes increased expression of MYC and Cyclin D1, stimulating cell cycling and proliferation [5]. Knock-down of PTPRZ1 decreased the amounts of nuclear β-catenin and suppressed cellular proliferation concomitant with a decrease in the expression of target genes: cyclin D1, c-myc, c-jun, fra-1, and CD44 in renal cell carcinoma [41]. However, studies in osteosarcoma were different from that in glioblastoma, and PTPRZ1-deficiency significantly enhanced osteosarcoma development with 19% Trp53-heterozygous mice, which suggest PTPRZ1 could function as a tumor suppressor function for osteosarcoma[21].

 Figure 3  Relevant molecules that interacted with PTPRZ1 from Cytoscape_3.6.0 (figure 3).
(Click on the image to enlarge.)

Cell-cell adhesion and cell migration

Cell-cell adhesion requires members of the cadherin-catenin families to link the highly conserved cadherin cytoplasmic domain to the actin-based cytoskeleton and to connect adjacent cells via the cadherin extracellular domains [28]. PTPRZ1-PTN interaction in liver cells modulates the tyrosine phosphorylation of factors, such as Src, focal adhesion kinase (FAK), PTEN, MEK, and Erk1/2, that control cell-cell adhesion, cell-matrix interactions and cell migration, including an increase in tyrosine- phosphorylated β-catenin, which is known to cause loss of cell-cell adhesion [28, 31, 52].
PTPRZ1-PTN is involved in regulating cell migration and metastasis on various substrata, including FAK, PI3K, MAPK, Src, PTEN, MEK, and Erk1/2, and integrin αvβ3 activity [2, 17, 29, 31]. PTPRZ1 gene knockdown increased the ability of human prostate cancer cells to migrate and invade in vitro and to metastasize in vivo [31]. PTPRZ1 gene knockdown interrupts hydrogen peroxide-induced cell migration[53] and PTPRZ1 gene knockdown in human umbilical vein endothelial cells (HUVEC) inhibited PTN-induced migration and tube formation on matrigel[34]. Treating PTPRZ1-positive ductular progenitor cells with PTN caused time-dependent accumulation of many tyrosine-phosphorylated proteins, including talin, tensin, paxillin, afadin and supervillin. These latter proteins control cell migration, and PTPRZ1-PTN interactions directly regulate the migratory activity of cultured human stem cells and liver progenitor cell [29].

Epithelial-to-mesenchymal transition (EMT)

PTPRZ1 was a negative regulator of EMT, where cancer cells lose polarity, cell-cell contacts and other epithelial characteristics, switching to a motile mesenchymal phenotype. Common EMT features include a loss of E-cadherin, elevated N-cadherin, integrins, Twist, Slug, and Snail expression, increased nuclear β-catenin, and gain of fibroblastoid morphology [31]. The EMT is a critical event in early development and a critical component of progression of malignant cells to a more aggressive phenotype [54]. In prostate cancer, the loss of PTPRZ1 gene expression initiated EMT and increased the ability of the cells to migrate and invade[31]. Phalloidin staining of PTPRZ1 gene knockdown cells revealed increased stress fiber formation and a concomitant decrease in the number of cortical actin fibers, marker of lamellipodia formation and a shift in cadherin expression from the E to the N-cadherin form, known to characterize the EMT-like phenotype and to promote cell motility[31].

Cancer stem cells

Tumor-associated macrophages (TAMs) secrete abundant PTN to stimulate glioma stem cells (GSCs) through PTPRZ1 thus promoting GBM malignant growth, and disrupting PTPRZ1 abrogated GSC maintenance and tumorigenic potential [55]. Knocking down PTPRZ1 gene altered the expression levels of SOX2, OLIG2, and POU3F2 and decreased the sphere- forming abilities in glioblastoma cells [19]. Another study found the knockdown of PTPRZ1 gene led to reduction of OCT4 and SOX2 transcripts by approximately 40%. OCT4 knockdown also resulted in 90% decrease of PTPRZ1 gene transcripts, consistent with the marked decrease of PTPRZ1 in differentiating embryonic stem cells[56]. PTN signaling via PTPRZ1 inhibits cell migration and acquisition of other mesenchymal cell characteristics, while PTPRZ1 alone promotes a migratory/mesenchymal phenotype when unopposed by PTN[52].

Others

The expression of PTPRZ1 was lower in the clofibrate plus radiation group than in the irradiated group in pancreatic cancer cells[47]. PTPRZ1 was involved in radiosensitization and downregulated after PPARα activation by clofibrate to sensitize pancreatic cancer cells to radiation [47]. PTPRZ1^-/- mice demonstrated marked social alteration with increased aggressivity, reminiscent of some positive symptoms of schizophrenia[57]. PTPRZ1-PTN also controls the timing of oligodendrocyte precursor cell differentiation, in which the CS moiety of PTPRZ1 maintains them in a monomeric active state until its ligand binding[22].

The network of PTPRZ1

In order to present the interaction of PTPRZ1 with other molecules, the network of PTPRZ1 based on the literatures we reviewed we conducted (Figure 4, Figure 5). Ectopic menin expression significantly repressed PTN transcription, and indirectly inhibited PTPRZ1 expression through repressing PTN expression, and further inhibits FAK and ERK1/2 phosphorylation[35]. PTPRZ1 is also a substrate for protein O-mannosyl glycosylation by POMGnT1 [58]. Rokavec et al. found inhibition of miR-200c in MCF-10a cells decreased PTPRZ1 expression, and overexpression of PTPRZ1 in MCF-10a-T cells decreased phosphorylation and increased expression of IkBa, resulting in accumulation of p65 in the nucleus of MCF-10a-T cells[49]. Fukada et al. identified several other substrates: Git1, p190, PIST, MAGI-3, Veli-3, Synj2bp, Syntrophin acidic1, Syntrophin basic1, MUPP1, Cardiac troponin T, hDKFZp434G232, KIAA0167, SPOP by a genetic method named the ''yeast substrate-trapping system''[43]. Additional targets of the PTPRZ1-PTN signaling pathway thus far identified include calmodulin, Fyn(Src family Kinase), β-adducin, P190RhoGAP, Notch-related transmembrane protein Delta/Notch-like EGF-related receptor(DNER), PI3K, Akt, FAK, ERK1/2, paxillin, PTEN, PIST, integrin-α5, integrin-αv, and integrin-β3, PKCα/β and IkBa, to functions of different cellular systems[1, 2, 5, 8, 16, 22, 24, 25, 29, 31, 34, 43, 49, 54, 59].

 Figure 4  Network based on the literatures we reviewed
(Click on the image to enlarge.)

 Figure 5  Signaling pathway based on the literatures we reviewed
(Click on the image to enlarge.)

Survival

Based on TCGA data, PTPRZ1 gene might be associated with overall survival (OS) in bladder urothelial carcinoma (BLCA), BRCA, CESC, COAD, GBM, LGG, liver hepatocellular carcinoma (LIHC), LUAD, pancreatic adenocarcinoma (PAAD), and SKCM, PTPRZ1 gene might be associated with disease free survival (DFS) in BLCA, CESC, COAD, head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), LGG, LUSC, mesothelioma (MESO), PAAD, READ, SKCM, thymoma (THYM), uterine carcinosarcoma (UCS) and uveal melanoma(UVM). High PTPRZ1 gene expression might be associated with better OS in BRCA, CESC, LUAD, PAAD, and SKCM, and low PTPRZ1 expression might be associated with better OS in BLCA, COAD, GBM, LGG, LIHC. High level of PTPRZ1 gene was associated better DFS in CESC, HNSC, LUSC, MESO, PAAD, SKCM, THYM, and UCS, while low level of PTPRZ1 gene was associated better DFS in BLCA, COAD, KIRC, LGG, READ and UVM (Figure 6).
PTPRZ1 was involved in survival signaling[60]. In human breast cancer, high expression of PTPRZ1 may be an independent risk indicator for triple- negative breast cancer (TNBC) recurrence and metastasis[61]. PTPRZ1 has a significant impact on survival of patients with oral squamous cell carcinoma, and patients with positive PTPRZ1 was associated with 8 times lower risk of death within 5 years than those with negative PTPRZ1[62].

The therapeutic values of PTPRZ1

PTPRZ1 might be a therapeutic target due to its role in cancer development, progression, and metastasis. Several inhibitors of PTPRZ1 or antibodies, including MY10, MY33-3[63], NAZ2329[19], were identified. Fujikawa et al. identified NAZ2329, a cell-permeable small molecule that allosterically inhibits PTPRZ1, which reduced the expression of SOX2 and abrogated the sphere-forming abilities in glioblastoma cells [19]. Protamine (PRM, a heparin antagonist) bound to the extracellular region of PTPRZ1, and functioned as a ligand mimetic of PTPRZ1, thereby suppressing its negative regulatory activity on oligodendrocyte differentiation[64]. However, few of them were studied in oncology field. Foehr et al. developed antibodies directed to PTPRZ1, which used the recombinant extracellular domain of human short PTPRZ1 to immunize mice and generate monoclonal antibodies that selectively recognize PTPRZ1 and bind to the antigen with low nanomolar affinities. These antibodies killed glioma cells in vitro when coupled to the cytotoxin saporin either directly or via a secondary antibody and significantly delay human glioma tumors in a mouse xenograft model[30]. Fujikawa et al. showed the intracellular delivery of SCB4380, the first potent inhibitor for PTPRZ1, by liposome carriers inhibited PTPRZ1 activity in glioblastoma cells, and thereby suppressed cell migration and proliferation in vitro and tumor growth in a rat allograft model[65]. Midkine and PTPRZ1 expression was detected in the gastric mucosal, submucosal and muscle layers, and rebamipide may protect the gastric mucosa by regulating midkine and PTPRZ1 expression[66].

Discussion

PTPRZ1 is a transmembrane protein tyrosine phosphatase and expressed in different tumor tissues. Based on TCGA data, PTPRZ1 was up-regulated in CESC, GBM, LGG, LUSC, and down-regulated in BRCA, COAD, PRAD, READ and STAD. Given the strong up-regulation of PTPRZ1, antagonization of PTPRZ1 expression and/or signaling may be a promising strategy to inhibit the tumor growth. For other cancers in which PTPRZ1 is down-regulation, activating PTPRZ1-dependent signaling could specifically target tumor cells. These indicate that pharmacological inhibition or activation of PTPRZ1 is a promising strategy for the treatment of several tumors. There were several drugs that target PTPRZ1, including PTPRZ1 antibodies[30], inhibitors (MY10, MY33-3[63], NAZ2329[19], protamine[64], and SCB4380[65]) and activators (rebamipide[66]). Most of available studies focused on the glioma therapy, except rebamipide. Rebamipide was found to increase PTPRZ1 and MK in stomach tissues and cell lines, but its role in cancer was not certificated, especially in those cancers that PTPRZ1 was down-regulated. These studies were conducted in vitro, and no clinical trials or observational studies were found till now. There is still a long way to go to translate available research results in vitro into clinical practice.
PTPRZ1 gene mutation accounts for a high proportion of cancer patients, especially in UCEC, the proportion could be up to 16.79%. Such a high proportion of cancer patients have PTPRZ1 mutations, so whether PTPRZ1 mutations could predict therapy efficacy or not deserved further research. Could the drugs that target PTPRZ1 be effective when PTPRZ1 was mutated? Or did PTPRZ1 mutation predict response of available treatment? Based on available literatures, not such a drug was found. Also no clinical or observational studies were found to assess the values of PTPRZ1 gene mutation in cancer therapy. In the future, the value of PTPRZ1 gene mutation in cancer therapy deserved to be researched and drugs that target patients with PTPRZ1 mutations were studied in literature. Tumors from patients harboring PTPRZ1-MET-fused glioblastoma are resistant to temozolomide therapy and have significantly compromised overall survival rates [11, 12]. Searching clinicaltrials.gov, only one trial about PTPRZ1 was retrieved without any study results, which was a phase I, open-label, dose-escalation study of c-Met inhibitor PLB1001 in patients with PTPRZ1-MET fusion gene positive recurrent high-grade gliomas. The prevalence, therapeutic and prognostic values of PTPRZ1-fusion genes in cancers were unclear and this needs further more researches.
The expression of PTPRZ1 in different kinds of cancer were different. This might imply different roles, however, the role of PTPRZ1 in cancer development, progression, and metastasis was not well studied. Based on available studies, PTPRZ1 functions in cell proliferation, cell adhesion and migration, EMT, cancer stem cells and treatment resistance by interacting with or binding to several molecules. The functional significance of the binding of molecules in PTPRZ1 signaling and their molecular pathways still remains unclear[2, 22]. Based on our review, these included PTN, midkine, interleukin-34, β-catenin, VEGF, NF-κB, HIF-2, PSD-95, MAGI-3, contactin and ErbB4. One of the most important ligands was PTN, and the PTPRZ1-PTN network was complex, which could activate PI3K and MAPK signaling pathway. Although Fukada et al. identified several other substrates by a genetic method named the ''yeast substrate-trapping system''[43], few of them were well studied in available literatures. More researches are needed to study what and how PTPRZ1 interacts with.
Based on TCGA data, PTPRZ1 gene might be associated with OS and DFS in several kinds of cancer, which implies that PTPRZ1 was involved in survival signaling[60]. The prognostic values of PTPRZ1 in different kinds of cancer were inconsistent, which imply that PTPRZ1 might play different roles in cancer progression. Our previous study showed high expression of PTPRZ1 may be an independent risk indicator for triple negative breast cancer recurrence and metastasis[61]. PTPRZ1 has a significant impact on survival in patients with oral squamous cell carcinoma, and patients with positive PTPRZ1 was associated with 8 times lower risk of death within 5 years than those with negative PTPRZ1[62]. The prognostic values of PTPRZ1 expression in other kinds of cancer were not assessed in available literatures, and further studies were required.
Although there were lots of studies focusing on PTPRZ1 in oncology field, lots of aspects of PTPRZ1 were not well studied. First, the prevalence of PTPRZ1-fusion genes and PTPRZ1 protein in cancers were unclear and their values in drug therapy and prognosis needs further research. Future studies should screen drugs for patients with PTPRZ1 gene mutations, PTPRZ1 fusion genes, and PTPRZ1 protein positivity. Second, pharmacological inhibition or activation of PTPRZ1 is a promising strategy for the treatment of several tumors. However, most of available studies focused on inhibitors or antibodies that target PTPRZ1 about gliomas in vitro and whether they were effective in other kinds of cancer which have up-regulation of PTPRZ1 expression. None of them were translated into clinical practice and the most effective drugs were not clear. For those kinds of cancer which have down-regulation of PTPRZ1 expression, PTPRZ1 activation drugs were not tested in cancer. Third, due to different expressions of PTPRZ1 in different tumor tissues, so whether the PTPRZ1 could be a biomarker for diagnosing cancer and distinguishing different kinds of cancer or not was unclear. Although a recent study showed PTPRZ1 was significantly over-expressed at the mRNA and protein levels in grade II/III glioma patients as compared to non-tumor samples[67], no studies showed PTPRZ1 could be used as a diagnostic biomarker. So the role of PTPRZ1 in diagnosing cancer should be considered in the future.
Our review is a descriptive study which described the research results of PTPRZ1 comprehensively based on Pubmed and EMBASE. Also the expression of PTPRZ1 gene, gene mutations, gene fusions, and their prognostic values in different kinds of cancers were analyzed. In this review, we could find out PTPRZ1 is expressed in different tumor tissues, and functions in cell proliferation, cell adhesion and migration, EMT, cancer stem cells and treatment resistance by interacting with or binding to several molecules. These included PTN, MK, IL-34, β-catenin, VEGF, NF-κB, HIF-2, PSD-95, MAGI-3, contactin and ErbB4. The PTPRZ1 network was complex, which could activate PI3K and MAPK signaling pathway. PTPRZ1 was involved in survival signalling and could predict the prognosis of several tumors. PTPRZ1 might be a therapeutic target in several kinds of cancers, however, available studies focused on the PTPRZ1 target for GBM in vitro. There is still a long way to go to translate available basic research results into clinical practice.
 Figure 6  Survival plot based on TCGA data (the plot

Proteiinityrosiinikinaasien ja tyrosiinifosfataasien tasapainossa on PTN tärkeä osatekijä.

https://www.pnas.org/content/103/47/17795
The balanced activities of tyrosine kinases (= fosforylases)  and tyrosine phosphatases dynamically regulate the steady-state levels of tyrosine phosphorylation of key proteins essential for many important cellular functions.
 The regulated disruption of this balance through growth factor and/or cytokine-activated receptor-transduced signals is an important mechanism of signal transduction but, when deregulated, is a mechanism frequently underlying different diseases and a major feature in the pathogenesis of many human malignancies (1).
 An important gap, however, is in understanding the mechanism of how different pathways and systems are coordinated to initiate the many different cellular functions required for normal cellular homeostasis, proliferation, and differentiation of cells.

(Kommenttini: Pleiotrofiinin osuus tämän  fundamentaalisen fosforylaation eöi  fosfaatin lisäämisen ja  fosfaatin poistamisen   tasapainon säätelyssä keskiössä! Artikkeli vuodelta 2006 taustana: )

Pleiotrophin disrupts calcium-dependent homophilic cell–cell adhesion and initiates an epithelial–mesenchymal transition

P. Perez-Pinera, S. Alcantara, T. Dimitrov, J. A. Vega, and T. F. Deuel

PNAS November 21, 2006 103 (47) 17795-17800; https://doi.org/10.1073/pnas.0607299103

Abstract

Regulation of the levels of tyrosine phosphorylation is essential to maintain the functions of proteins in different signaling pathways and other cellular systems, but how the steady-state levels of tyrosine phosphorylation are coordinated in different cellular systems to initiate complex cellular functions remains a formidable challenge. The receptor protein tyrosine phosphatase (RPTP)β/ζ is a transmembrane tyrosine phosphatase whose substrates include proteins important in intracellular and transmembrane protein-signaling pathways, cytoskeletal structure, cell–cell adhesion, endocytosis, and chromatin remodeling. 

Pleiotrophin (PTN the protein and Ptn the gene) is a ligand for RPTPβ/ζ;

 PTN inactivates RPTPβ/ζ, leaving unchecked the continued endogenous activity of tyrosine kinases that increase phosphorylation of the substrates of RPTPβ/ζ at sites dephosphorylated by RPTPβ/ζ in cells not stimulated by PTN.

 Thus, through the regulation of the tyrosine phosphatase activity of RPTPβ/ζ, the PTN/RPTPβ/ζ signaling pathway coordinately regulates the levels of tyrosine phosphorylation of proteins in many cellular systems. 

We now demonstrate that PTN disrupts cytoskeletal protein complexes, ablates calcium-dependent homophilic cell–cell adhesion, stimulates ubiquitination and degradation of N-cadherin, reorganizes the actin cytoskeleton, and induces a morphological epithelial–mesenchymal transition (EMT) in PTN-stimulated U373 cells. 

The data suggest that increased tyrosine phosphorylation of the different substrates of RPTPβ/ζ in PTN-stimulated cells alone is sufficient to coordinately stimulate the different functions needed for an EMT; it is possible that PTN initiates an EMT in cells at sites where PTN is expressed in development and in malignant cells that inappropriately express Ptn.

• receptor protein tyrosine phosphataseβ/ζ
• glioblastoma
• cadherin
• β-catenin
• cytoskeleton

 The balanced activities of tyrosine kinases and tyrosine phosphatases dynamically regulate the steady-state levels of tyrosine phosphorylation of key proteins essential for many important cellular functions. The regulated disruption of this balance through growth factor and/or cytokine-activated receptor-transduced signals is an important mechanism of signal transduction but, when deregulated, is a mechanism frequently underlying different diseases and a major feature in the pathogenesis of many human malignancies (1). An important gap, however, is in understanding the mechanism of how different pathways and systems are coordinated to initiate the many different cellular functions required for normal cellular homeostasis, proliferation, and differentiation of cells.

 The diverse substrates of the receptor protein tyrosine phosphatase (RPTP)β/ζ (2) include β-catenin (2), β-adducin (3, 4), Fyn (5), GIT1/Cat-1 (6), and P190RhoGAP (7), indicating that RPTPβ/ζ is promiscuous in substrate specificity, but through its activity, is critically positioned to coordinately regulate the steady-state levels of tyrosine phosphorylation of proteins in different signaling networks and cellular systems. 

Pleiotrophin (PTN the protein and Ptn the gene) is a secreted, highly conserved cytokine (8, 9) that signals through inactivation of RPTPβ/ζ; as a consequence, PTN coordinately increases tyrosine phosphorylation of the many substrates of RPTPβ/ζ through persistent activity of the tyrosine kinases that phosphorylate the same sites that are dephosphorylated by RPTPβ/ζ in cells not stimulated by PTN.

 The diverse substrates regulated through the PTN/RPTPβ/ζ signaling pathway thus are likely to account for the diverse functions signaled by PTN in different cellular systems and in the different malignant cell lines with inappropriate expression of Ptn (10).

2017 siRNA hiljennetty pleiotrofiini hiirikokeissa

https://www.ncbi.nlm.nih.gov/pubmed/28562667 Abstract

Pleiotrophin (PTN) is a secreted cytokine that is expressed in various cancer cell lines and human tumor such as colon cancer, lung cancer, gastric cancer and melanoma. It plays significant roles in angiogenesis, metastasis, differentiation and cell growth. The expression of PTN in the adult is limited to the hippocampus in an activity-dependent manner, making it a very attractive target for cancer therapy. RNA interference (RNAi) offers great potential as a new powerful therapeutic strategy based on its highly specific and efficient silencing of a target gene. However, efficient delivery of small interfering RNA (siRNA) in vivo remains a significant hurdle for its successful therapeutic application. In this study, we first identified, on a cell-based experiment, applying a 1:1 mixture of two PTN specific siRNA engenders a higher silencing efficiency on both mRNA and protein level than using any of them discretely at the same dose. As a consequence, slower melanoma cells growth was also observed for using two specific siRNA combinatorially. To establish a robust way for siRNA delivery in vivo and further investigate how silence of PTN affects tumor growth, we tested three different methods to deliver siRNA in vivo: first non-targeted in-vivo delivery of siRNA via jetPEI; second lung targeted delivery of siRNA via microbubble coated jetPEI; third tumor cell targeted delivery of siRNA via transferrin-polyethylenimine (Tf-PEI). As a result, we found that all three in-vivo siRNAs delivery methods led to an evident inhibition of melanoma growth in non-immune deficiency C57BL/6 mice without a measureable change of ALT and AST activities. Both targeted delivery methods showed more significant curative effect than jetPEI. The lung targeted delivery by microbubble coated jetPEI revealed a comparable therapeutic effect with Tf-PEI, indicating its potential application for target delivery of siRNA in vivo.

PMID:

28562667

PMCID:

PMC5451024

DOI:

10.1371/journal.pone.0177964

[Indexed for MEDLINE]

Free PMC Article

• ( Kommentti 5.9. 2019. miksi  hiljentää PTN tuumoritapauksissa?  PTN vaikuttaa EMT prosesiin, koska tuumori erittää PTN, jolloin sen märä aiheutta  entsyymien fosfaatin käsitelyyn epätasapainoa, joka suosii  EMT, tuumorikasvua ja migroitumista, PTN- vaikutusakseli tuumoreissa voi olla myös kemoresistenssin taustalla)
•  Ajatuksiani: AD biomerkitsijänä toimivassa  C-terminaalisessa peptidisekvenssissä on runsaasti lysiiniä K, jolloin  kiinnostaa  sen mahdolliset  ubikitiiniligaasit ja deubkitinaasit (DUBs)  ja niiden toiminta.  PTN itse edistää N-kadheriinin ubikitinaatiota. 
• AD taudissa on olennaista   jumittunut fosfaattiaineenvaihdunta.

PTN,(7q33), pleiotrofiinigeeni ja sen koodaama pleitrofiini

https://www.ncbi.nlm.nih.gov/gene/5764
Tällä PTN- geenillä on muitakin nimiä.  HARP; HBBM; HBNF; HBGF8; NEGF1; OSF-1; HB-GAM; HBGF-8; HBNF-1.
Geenin koodaama påroteiini on eräs erittynyt hepariinia sitova kasvutekijä.(HBGF8). Tällä proteiinilla on merkitseviä osia solukasvussa ja solun elossapysymisessä, solun migroitumisessa, angiogeneesissä ja tumorigeneesissä.
Tästä geenistä tuolee monenlaisia  transkriptivariantteja vaihtoehtoispleissuksella ( silmukoinnilla)  ja vaihtoehtoisia promoottoreita käyttämällä.
Geeniä ilmentyy  laajalti aivoissa, prostatassa ja 17 muussa kudoksessa.

PTN

Official Full Name

pleiotrophin

Gene type

protein coding

RefSeq status

REVIEWED

Organism

Homo sapiens

Also known as

HARP; HBBM; HBNF; HBGF8; NEGF1; OSF-1; HB-GAM; HBGF-8; HBNF-1

Summary

The protein encoded by this gene is a secreted heparin-binding growth factor. The protein has significant roles in cell growth and survival, cell migration, angiogenesis and tumorigenesis. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Oct 2016]

Expression: Broad expression in brain (RPKM 83.5), prostate (RPKM 56.7) and 17 other tissues See more

Orthologs: mouse all.

Preferred Names

pleiotrophin

Names

heparin affin regulatory protein (HARP)

heparin-binding brain mitogen (HBBM)

heparin-binding growth factor 8 (HBGF8)

heparin-binding growth-associated molecule (HB-GAM)

heparin-binding neurite outgrowth promoting factor

heparin-binding neurite outgrowth-promoting factor 1 (HBNF-1)

osteoblast-specific factor 1 (OSF-1)

pleiotrophin (PTN) 

 (heparin binding growth factor 8, neurite growth-promoting factor 1(NEGF-1)

Peptidestructure (Rakenne-esimerkki: isoformi 1 prekursori)  

https://www.ncbi.nlm.nih.gov/protein/NP_001308315.1 

 History:  mentioned first  1990:

REFERENCE   10 (residues 1 to 168)
  AUTHORS   Tezuka K, Takeshita S, Hakeda Y, Kumegawa M, Kikuno R and
            Hashimoto-Gotoh T.
  TITLE     Isolation of mouse and human cDNA clones encoding a protein
            expressed specifically in osteoblasts and brain tissues
  JOURNAL   Biochem. Biophys. Res. Commun. 173 (1), 246-251 (1990)

Gene PTN cloned 1992:  HBGF, homologous to a cytokine.

 REFERENCE   8  (residues 1 to 168)
  AUTHORS   Milner PG, Shah D, Veile R, Donis-Keller H and Kumar BV.
  TITLE     Cloning, nucleotide sequence, and chromosome localization of the
            human pleiotrophin gene
  JOURNAL   Biochemistry 31 (48), 12023-12028 (1992)
   PUBMED   1457401
REFERENCE   9  (residues 1 to 168)
  AUTHORS   Wellstein A, Fang WJ, Khatri A, Lu Y, Swain SS, Dickson RB, Sasse
            J, Riegel AT and Lippman ME.
  TITLE     A heparin-binding growth factor secreted from breast cancer cells
            homologous to a developmentally regulated cytokine
  JOURNAL   J. Biol. Chem. 267 (4), 2582-2587 (1992)
   PUBMED   1733956

PTN-HERV  insertio havaittu 1996. 

REFERENCE   6  (residues 1 to 168)
  AUTHORS   Schulte AM, Lai S, Kurtz A, Czubayko F, Riegel AT and Wellstein A.
  TITLE     Human trophoblast and choriocarcinoma expression of the growth
            factor pleiotrophin attributable to germ-line insertion of an
            endogenous retrovirus (ERV, Human ERV , HERV) 
  JOURNAL   Proc. Natl. Acad. Sci. U.S.A. 93 (25), 14759-14764 (1996)
   PUBMED   8962128

2017  noticed:  NK-cells secrete pleiotrophin.

REFERENCE   5  (residues 1 to 168)
  AUTHORS   Fu B, Zhou Y, Ni X, Tong X, Xu X, Dong Z, Sun R, Tian Z and Wei H.
  TITLE     Natural Killer Cells Promote Fetal Development through the
            Secretion of Growth-Promoting Factors
  JOURNAL   Immunity 47 (6), 1100-1113 (2017)
   PUBMED   29262349
  REMARK    GeneRIF: NK cells promote fetal development through the secretion
            of growth-promoting factors, pleiotrophin and osteoglycin.

 2018 noticed: pleitrophin  a prognostic  factor in cancer. 

 REFERENCE   3  (residues 1 to 168)

 AUTHORS   Zhou J, Yang Y, Zhang Y, Liu H and Dou Q.
  TITLE     A meta-analysis on the role of pleiotrophin (PTN) as a prognostic
            factor in cancer
  JOURNAL   PLoS ONE 13 (11), e0207473 (2018)

2019 noticed a mechanism behind chemotherapy resistence in Ca mammae. 

 
REFERENCE   2  (residues 1 to 168)
  AUTHORS   Huang P, Ouyang DJ, Chang S, Li MY, Li L, Li QY, Zeng R, Zou QY, Su
            J, Zhao P, Pei L and Yi WJ.
  TITLE     Chemotherapy-driven increases in the CDKN1A/PTN/PTPRZ1 axis promote
            chemoresistance by activating the NF-kappaB pathway in breast
            cancer cells
  JOURNAL   Cell Commun. Signal 16 (1), 92 (2018)
   PUBMED   30497491

2019 noticed that PTN inhibits PTPase."Protein tyrosine phosphatase receptor type Z

 (PTPRZ) maintains oligodendrocyte precursor cells (OPCs) in an undifferentiated

 state. The inhibition of PTPase by its ligand pleiotrophin
 (PTN) promotes OPC differentiation;  the substrate molecules of
 PTPRZ involved in the differentiation ..elucidated in detail.. concluded that 

the PTN-PTPRZ signal stimulates OPC differentiation 
partly by enhancing the tyrosine phosphorylation of (adaptor) AFAP1L2 in order to 
activate the PI3K-AKT pathway.

 PTN isoform aminoacidsequence:

 ORIGIN      
        1 mqaqqyqqqr rkfaaaflaf ifilaavdta eagkkekpek kvkksdcgew qwsvcvptsg
       61 dcglgtregt rtgaeckqtm ktqrckipcn wkkqfgaeck yqfqawgecd lntalktrtg
      121 slkralhnae cqktvtiskp cgkltkpkpq aeskkkkkeg kkqekmld
//

  sig_peptide     1..32   (        1 mqaqqyqqqr rkfaaaflaf ifilaavdta ea)
                     /inference="COORDINATES: ab initio prediction:SignalP:4.0"
                     /calculated_mol_wt=3647
     mat_peptide     33..168
                     /product="Pleiotrophin"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="propagated from UniProtKB/Swiss-Prot (P21246.1)"
                     /calculated_mol_wt=15313
     Region          47..131
                     /region_name="PTN_MK_N" (47 qwsvcvptsg
       61 dcglgtregt rtgaeckqtm ktqrckipcn wkkqfgaeck yqfqawgecd lntalktrtg
      121 slkralhnae c) 
                     /note="PTN/MK heparin-binding protein family, N-terminal
                     domain; cl02505"
                     /db_xref="CDD:321956"
     Region          92..99    (92 kkqfgaec)
                     /region_name="Chondroitin sulfate binding.
                     {ECO:0000269|PubMed:26896299}"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="propagated from UniProtKB/Swiss-Prot (P21246.1)"
     Region          123..131  (123 kralhnae c)  
                     /region_name="Chondroitin sulfate binding.
                     {ECO:0000269|PubMed:26896299}"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="propagated from UniProtKB/Swiss-Prot (P21246.1)"
     Region          147..168  ( 147 pkpq aeskkkkkeg kkqekmld)
                     /region_name="Chondroitin sulfate A binding.
                     {ECO:0000269|PubMed:26896299}"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="propagated from UniProtKB/Swiss-Prot (P21246.1)"
     CDS             1..168
                     /gene="PTN"
                     /gene_synonym="HARP; HB-GAM; HBBM; HBGF-8; HBGF8; HBNF;
                     HBNF-1; NEGF1; OSF-1"
                     /coded_by="NM_001321386.2:534..1040"
                     /note="isoform 1 precursor is encoded by transcript
                     variant 2"
                     /db_xref="CCDS:CCDS5844.1"
                     /db_xref="GeneID:5764"
                     /db_xref="HGNC:HGNC:9630"
                     /db_xref="MIM:162095"

 

  PubMed ref.

Bibliography

Related articles in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Proliferative  vitreoretinopathy(PVR) and PTN

 https://link.springer.com/article/10.1007%2Fs00417-016-3582-9

kommenttini GU uusi väitöskirja 4.9. 2019 :

AD biomerkitsijänä toimii  eräs C-terminaalinen fragmentti pleiotrofiinia:

 https://www.ncbi.nlm.nih.gov/pubmed?cmd=Retrieve&db=PubMed&list_uids=29042634 Abstract

We present a new, quantification-driven proteomic approach to identifying biomarkers. In contrast to the identification-driven approach, limited in scope to peptides that are identified by database searching in the first step, all MS data are considered to select biomarker candidates. The endopeptidome of cerebrospinal fluid from 40 Alzheimer's disease (AD) patients, 40 subjects with mild cognitive impairment, and 40 controls with subjective cognitive decline was analyzed using multiplex isobaric labeling. Spectral clustering was used to match MS/MS spectra. The top biomarker candidate cluster (215% higher in AD compared to controls, area under ROC curve = 0.96) was identified as a fragment of pleiotrophin located near the protein's C-terminus. Analysis of another cohort (n = 60 over four clinical groups) verified that the biomarker was increased in AD patients while no change in controls, Parkinson's disease or progressive supranuclear palsy was observed. The identification of the novel biomarker pleiotrophin 151-166

( 151 aeskkkkkeg kkqekm) 

demonstrates that our quantification-driven proteomic approach is a promising method for biomarker discovery, which may be universally applicable in clinical proteomics.

PMID:

29042634

PMCID:

PMC5645330

DOI:

10.1038/s41598-017-13831-0

ERV ja niiden osuus ihmisen sairauksissa?

Endogeeniset retrovirukset ja niiden merkitys ihmiselle?
https://www.ncbi.nlm.nih.gov/books/NBK6235/

Mikä on pleiotrofiini, PTN?

Best matches for pleiotrophin:

Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma. Qin EY et al. Cell. (2017)

 

Pleiotrophin regulates microglia-mediated neuroinflammation. Fernández-Calle R et al. J Neuroinflammation. (2017)

 

From top to bottom: midkine and pleiotrophin as emerging players in immune regulation. Sorrelle N et al. J Leukoc Biol. (2017)

 Asiasta on 754 artikkelia PubMed hakulaitteessa ja parhaat matchit ovat kolme  ylhäällä mainittua.

20 tuoreinta  ovat tässä: 

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Select item 314168341.

A head-to-toe dimerization has physiological relevance for ligand-induced inactivation of protein tyrosine receptor type Z.

Fujikawa A, Sugawara H, Tanga N, Ishii K, Kuboyama K, Uchiyama S, Suzuki R, Noda M.

J Biol Chem. 2019 Aug 15. pii: jbc.RA119.007878. doi: 10.1074/jbc.RA119.007878. [Epub ahead of print]

PMID:

31416834

Free Article

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Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss.

Nikolakopoulou AM, Montagne A, Kisler K, Dai Z, Wang Y, Huuskonen MT, Sagare AP, Lazic D, Sweeney MD, Kong P, Wang M, Owens NC, Lawson EJ, Xie X, Zhao Z, Zlokovic BV.

Nat Neurosci. 2019 Jul;22(7):1089-1098. doi: 10.1038/s41593-019-0434-z. Epub 2019 Jun 24.

PMID:

31235908

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Sharpening the tools for pericyte research.

Berthiaume AA, Shih AY.

Nat Neurosci. 2019 Jul;22(7):1041-1043. doi: 10.1038/s41593-019-0437-9. No abstract available.

PMID:

31235904

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The Expression, Functions, Interactions and Prognostic Values of PTPRZ1: A Review and Bioinformatic Analysis.

Xia Z, Ouyang D, Li Q, Li M, Zou Q, Li L, Yi W, Zhou E.

J Cancer. 2019 Apr 2;10(7):1663-1674. doi: 10.7150/jca.28231. eCollection 2019. Review.

PMID:

31205522

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Pleiotrophin regulates functional heterogeneity of microglia cells in EAE animal models of multiple sclerosis by activating CCr-7/CD206 molecules and functional cytokines.

Miao J, Wang F, Wang R, Zeng J, Zheng C, Zhuang G.

Am J Transl Res. 2019 Apr 15;11(4):2013-2027. eCollection 2019.

PMID:

31105814

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Luteolin suppresses colorectal cancer cell metastasis via regulation of the miR‑384/pleiotrophin axis.

Yao Y, Rao C, Zheng G, Wang S.

Oncol Rep. 2019 Jul;42(1):131-141. doi: 10.3892/or.2019.7136. Epub 2019 Apr 24.

PMID:

31059061

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Select item 310542777.

Inhibition of RPTPβ/ζ blocks ethanol-induced conditioned place preference in pleiotrophin knockout mice.

Fernández-Calle R, Gramage E, Zapico JM, de Pascual-Teresa B, Ramos A, Herradón G.

Behav Brain Res. 2019 Sep 2;369:111933. doi: 10.1016/j.bbr.2019.111933. Epub 2019 May 1.

PMID:

31054277

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Connecting Metainflammation and Neuroinflammation Through the PTN-MK-RPTPβ/ζ Axis: Relevance in Therapeutic Development.

Herradon G, Ramos-Alvarez MP, Gramage E.

Front Pharmacol. 2019 Apr 12;10:377. doi: 10.3389/fphar.2019.00377. eCollection 2019. Review.

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31031625

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Heparin-Modified Collagen Gels for Controlled Release of Pleiotrophin: Potential for Vascular Applications.

Copes F, Chevallier P, Loy C, Pezzoli D, Boccafoschi F, Mantovani D.

Front Bioeng Biotechnol. 2019 Apr 9;7:74. doi: 10.3389/fbioe.2019.00074. eCollection 2019.

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FEBS J. 2019 Aug;286(15):2921-2936. doi: 10.1111/febs.14830. Epub 2019 Apr 10. Review.

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Expression of the heparin-binding growth factors Midkine and pleiotrophin during ocular development.

Cui R, Lwigale P.

Gene Expr Patterns. 2019 Jun;32:28-37. doi: 10.1016/j.gep.2019.02.001. Epub 2019 Feb 27.

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The primate-specific peptide Y-P30 regulates morphological maturation of neocortical dendritic spines.

Neumann JR, Dash-Wagh S, Jack A, Räk A, Jüngling K, Hamad MIK, Pape HC, Kreutz MR, Puskarjov M, Wahle P.

PLoS One. 2019 Feb 13;14(2):e0211151. doi: 10.1371/journal.pone.0211151. eCollection 2019.

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The PTN-PTPRZ signal activates the AFAP1L2-dependent PI3K-AKT pathway for oligodendrocyte differentiation: Targeted inactivation of PTPRZ activity in mice.

Tanga N, Kuboyama K, Kishimoto A, Kiyonari H, Shiraishi A, Suzuki R, Watanabe T, Fujikawa A, Noda M.

Glia. 2019 May;67(5):967-984. doi: 10.1002/glia.23583. Epub 2019 Jan 22.

PMID:

30667096

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Pleiotrophin: Analysis of the endothelialisation potential.

Copes F, Ramella M, Fusaro L, Mantovani D, Cannas M, Boccafoschi F.

Adv Med Sci. 2019 Mar;64(1):144-151. doi: 10.1016/j.advms.2018.08.007. Epub 2019 Jan 17.

PMID:

30660899

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Genome-wide screening identifies oncofetal lncRNA Ptn-dt promoting the proliferation of hepatocellular carcinoma cells by regulating the Ptn receptor.

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Oncogene. 2019 May;38(18):3428-3445. doi: 10.1038/s41388-018-0643-z. Epub 2019 Jan 14.

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Serum pleiotrophin as a diagnostic and prognostic marker for small cell lung cancer.

Xu C, Wang Y, Yuan Q, Wang W, Chi C, Zhang Q, Zhang X.

J Cell Mol Med. 2019 Mar;23(3):2077-2082. doi: 10.1111/jcmm.14116. Epub 2019 Jan 11.

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30635982

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Neural Stem Cells Behave as a Functional Niche for the Maturation of Newborn Neurons through the Secretion of PTN.

Tang C, Wang M, Wang P, Wang L, Wu Q, Guo W.

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Chemotherapy-driven increases in the CDKN1A/PTN/PTPRZ1 axis promote chemoresistance by activating the NF-κB pathway in breast cancer cells.

Huang P, Ouyang DJ, Chang S, Li MY, Li L, Li QY, Zeng R, Zou QY, Su J, Zhao P, Pei L, Yi WJ.

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A meta-analysis on the role of pleiotrophin (PTN) as a prognostic factor in cancer.

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Pleiotrophin deletion alters glucose homeostasis, energy metabolism and brown fat thermogenic function in mice.

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