PTPN9 (protein tyrosine phosphatase, non-receptor type 9)

2016-11-01   Barnabas Nyesiga , Anette Gjörloff Wingren 

Biomedical science, Health and society, Malmö University, Malmö, Sweden nyesigabarnabas@gmail.com; anette.gjorloff-wingren@mah.se

Identity

HGNC
LOCATION
15q24.2
LOCUSID
ALIAS
MEG2,PTPMEG2
FUSION GENES

Abstract

Review on PTPN9, with data on DNA, on the protein encoded, and where the gene is implicated.

DNA/RNA

Note

PTPN9 was originally cloned by screening libraries of the MEG-01 megakaryocyte leukemia cell line and of human umbilical vein endothelial cells (Gu 1992).

Description

The PTPN9 gene was mapped to chromosome 15q24.2 based on an alignment of the PTPN9 sequence (GenBank BC010863) with the genomic sequence (GRCh37).

Transcription

MEG2 mRNA detected in 12 cell lines gave an indication that the protein tyrosine phosphatase (PTP) is widely expressed. A 4-kb RNA as analysed by Northern blot analysis was found in a variety of cell lines, indicating widespread expression of the gene (Gu 1992).

Proteins

Note

NOTE PTPN9 has a conserved PTP catalytic domain, and an NH2-terminal lipid-binding domain homologous to Sec14p, a yeast protein with phosphatidylinositol transferase activity, which is unique among PTPs (Gu 1992). The N-terminal 254 amino acids are about 28% identical to cellular retinaldehyde binding protein-1 (RLBP1; 180090) and 24% identical to the yeast protein SEC14p. The former is a carrier protein for 11-cis-retinaldehyde or 11-cis-retinol found in the retina and pineal gland, and the latter is a phosphatidylinositol transfer protein required for protein secretion from the Golgi apparatus. The PTPN9 cDNA encodes a 593-amino acid protein that has no apparent signal or transmembrane domains but does include a C-terminal region with a catalytic domain that shows 30-40% identity with other PTPs (http://www.omim.org/entry/600768).
Atlas Image
Figure 1. Schematic diagram of recombinant PTPN9 protein (Adapted from Zhao et al. 2003).The open and solid bars indicate SEC14 lipid-binding domain and PTP catalytic domain, respectively.

Description

PTPN9 is a 68-kDa, class I, cysteine-based, non-receptor PTP is widely expressed in many cell types including the brain and leukocytes (Gu 1992, Saito 2007). In these cells, most of the PTPN9 is located on the cytoplasmic face of secretory vesicles (Gjörloff-Wingren 2000, Wang 2002, Kruger 2002 and Huynh 2004). On the cytoplasmic face of the enclosing membrane of secretory vesicles, PTPN9 regulates vesicle size by promoting homotypic vesicle fusion through dephosphorylating NSF (N-ethylmaleimide-sensitive factor), a key regulator of vesicle fusion (Saito 2007). PTPN9 structural uniqueness among mammalian PTPs lies in the fact that it contains a domain in its N terminus with homology to yeast Sec14p, a phosphatidylinositol-binding protein (Sha 1998). This Sec14p homology (SEC14) domain of PTPN9 (Fig 1) is known to bind phosphoinositides (Kruger 2002, Huynh 2003, Krugmann 2002), a process that leads into enzymatic activation of the phosphatase domain (Kruger 2002, Huynh 2003). Using a series of deletion mutants, Saito et al identified the N-terminal SEC14 domain of PTPN9, residues 1-261, as the region containing the secretory vesicle targeting signal (Saito 2007). The SEC14 domain, alone or attached to a heterologous protein, was localized to intracellular vesicle membranes. In addition, two proteins, mannose 6-phosphate receptor-interacting protein PLIN3 (TIP47) and ARFIP2 Arfaptin2 altered PTPN9 localization when overexpressed, and elimination of TIP47 resulted in loss of PTPN9 function. It has been shown that the truncated form of the N-terminal SEC14 domain of PTPN9 has a significantly higher activity than the full-length enzyme (Qi 2002, Kruger 2002). By using lipid-membrane overlay and liposome binding assays, a specific binding of PTPN9 to phosphatidylserine was demonstrated (Zhao 2003). The binding was found to be mediated by the SEC14 domain. In intact cells, the SEC14 domain was found to play a prominent role in the localization of PTPN9 to the perinuclear region. Moreover, PTPN9 may play an important role through specific binding of phosphatidylserine, in regulating the signaling processes associated with phagocytosis of apoptotic cells (Zhao 2003).

Expression

The enzyme is expressed in many cell types (Gu 1992, Saito 2007), including at low levels in Jurkat T cells (Gjörloff-Wingren 2000), mast cells and lymphocytes (Wang 2002, Wang 2005).

Localisation

Reports have shown PTPN9 residence on internal membranes, including secretory vesicles and granules in neutrophils and lymphocytes where it regulates secretory vesicle size and fusion (Gjörloff-Wingren 2000, Wang 2002, Huynh 2003, Wang 2005). It is possible that once engulfed by phagocytes, a high level of phosphatidylserine in the outer membrane of apoptotic cells may alter the distribution of PTPN9 in phagocytes (Zhao 2003). It has been suggested that the physiological function of PTPN9 may be to regulate formation of secretory vesicles of a defined and cell type-specific size (Wang 2002). PTPN9 expression is higher in mast cells (granule size 400-600 nm) than in lymphocytes (granule size 200-300 nm) (Wang 2002).

Function

It was proposed that PTPN9 promotes homotypic fusion of immature secretory vesicles, which is a major step in the formation of these vesicles from post-Golgi transport vesicles containing cargo destined for secretion (Wang 2002, Huynh 2004, Huynh 2003, Wang 2005, Mustelin 2004). Additionally, PTPN9 may represent a novel connection between dephosphorylation of tyrosine and the regulation of secretory vesicles in hematopoietic cells (Wang 2002). Moreover, the possibility of PTPN9 expression in controlling the extent of the secretory apparatus of hematopoietic cells was proposed. Huyhn et al showed that PTPN9 regulates homotypic fusion of immature secretory vesicles by dephosphorylating the key regulator of vesicle fusion, N-ethylmaleimide-sensitive factor (NSF) (Huyhn 2004). PTPN9 can also regulate embryonic development (Wang 2005) and expansion of erythroid cells (Xu 2003). Studies have further demonstrated that PTPN9 controls insulin production, beta cell growth or insulin signaling by reducing insulin receptor (INSR) dephosphorylation in type II diabetes (Cho 2006, Chen 2010). Other studies have shown that PTPN9 promotes dephosphorylation of epidermal growth factor receptor (EGFR) and the receptor tyrosine protein kinase ERBB2, thereby impairing the activation of signal transducer and activator of transcription 3 (STAT3) (Yuan 2010) and STAT5 (Yuan 2010, Furth 2011) in breast cancer cells. From their observations, it was suggested that PTPN9-mediated modulation of secretory vesicle genesis and function plays an essential role in neural tube, vascular, and bone development as well as activation may participate in the transfer of hydrophobic ligands or may be involved in Golgi-related functions (Gu 1992). PTPN9 appears to regulate a balance by promoting fusion (anterograde transport) and reducing condensation (retrograde transport), thus increasing the size of secretory vesicles (Saito 2007). In addition, it was recently shown that the transport of neurotrophin receptor TRKA ( NTRK1) to the cell surface requires PTPN9 activity (Zhang 2016). Trk A is a novel substrate of PTPN9 and is dephosphorylated at both the kinase activation domain (Tyr674/675) and the signaling effector binding site (Tyr490). The studies were performed in neurite outgrowth and cortical neurons (Zhang 2016).

Implicated in

Entity name
Breast cancer
Note
ErbB family of the receptor protein-tyrosine kinase plays an important role in the progression of human cancers including breast cancer. Among the 43 human protein-tyrosine phosphatases analysed, Yuan 2010 discovered the knockdown of PTPN9 to significantly increase ERBB2 tyrosine phosphorylation in the SKBR3 breast cancer cell line. Additionally, knockdown of PTPN9 expression enhances tyrosine phosphorylation of the ErbB1/EGFR in the MDA-MB-231 breast cancer cell line. Their data suggested PTPN9 to be a negative regulator of breast cancer cells through targeting ErbB2 and EGFR and inhibiting STAT activation (Yuan 2010).
Entity name
Hepatocellular carcinoma
Note
PTPN9 expression was down-regulated in human hepatocellular carcinoma (HCC) tumor tissues, associate with worsened overall survival in HCC patients (Hu 2016). Depletion ofPTPN9 inhibits the apoptosis and promotes the proliferation of HCC cells.
Entity name
Diabetes
Note
PTPN9 have been identified as a modulator of insulin-dependent FOXO1 subcellular localization (Cho 2006). Ectopic expression of PTPN9 in cells to suppress insulin-induced phosphorylation of the insulin receptor, while RNAi-mediated reduction of PTPN9 transcript levels enhanced insulin action. Their findings implicated PTPN9 as a mediator of blood glucose homeostasis through antagonism of insulin signaling, and proposed modulation of PTPN9 activity to be an adequate strategy in type 2 diabetes treatment. Indeed, treatment with PTPN9 inhibitors can lead to enhanced insulin action both in vitro and in vivo (Zhang 2012).
Entity name
Hematopoiesis
Note
Xu et al identified PTPN9 to be contained in erythroid colony-forming cells (ECFCs) from polycythemia vera (PV), a human clonal myeloproliferative disorder (Xu 2003). Increased activity of PTPN9 in PV cells to be attributed to its elevated distribution in the membrane fraction. Additionally, the findings showed that PTPN9 plays a major role in the development of erythroid cells.
Entity name
Immunodeficiency
Note
PTPN9-/- mice were reported to be immunodeficient as they displayed severe developmental malformations, such as defective skull formation and intracranial bleeding (Wang 2005). The mice remained small and the majority of them died before birth or within the first neonatal days. Furthermore, they detected defective platelet activation and very little interleukin-2 secretion in these mice. They attributed all these abnormalities to defective PTPN9 secretion.

Bibliography

Pubmed IDLast YearTitleAuthors
204014542010[Research progress of several protein tyrosine phosphatases in diabetes].Chen M et al
166792942006Identification of the tyrosine phosphatase PTP-MEG2 as an antagonist of hepatic insulin signaling.Cho CY et al
220183982011Signal transducer and activator of transcription 5 as a key signaling pathway in normal mammary gland developmental biology and breast cancer.Furth PA et al
109409332000Subcellular localization of intracellular protein tyrosine phosphatases in T cells.Gjörloff-Wingren A et al
15574041992Cloning and expression of a cytosolic megakaryocyte protein-tyrosine-phosphatase with sequence homology to retinaldehyde-binding protein and yeast SEC14p.Gu M et al
267154392016Downregulated Expression of PTPN9 Contributes to Human Hepatocellular Carcinoma Growth and Progression.Hu B et al
153225542004Control of vesicle fusion by a tyrosine phosphatase.Huynh H et al
146628692003Homotypic secretory vesicle fusion induced by the protein tyrosine phosphatase MEG2 depends on polyphosphoinositides in T cells.Huynh H et al
117115292002Protein-tyrosine phosphatase MEG2 is expressed by human neutrophils. Localization to the phagosome and activation by polyphosphoinositides.Kruger JM et al
118045892002Identification of ARAP3, a novel PI3K effector regulating both Arf and Rho GTPases, by selective capture on phosphoinositide affinity matrices.Krugmann S et al
152200042004Protein tyrosine phosphatases in T cell physiology.Mustelin T et al
121120182002Purification and characterization of protein tyrosine phosphatase PTP-MEG2.Qi Y et al
173871802007Association of protein-tyrosine phosphatase MEG2 via its Sec14p homology domain with vesicle-trafficking proteins.Saito K et al
94612211998Crystal structure of the Saccharomyces cerevisiae phosphatidylinositol-transfer protein.Sha B et al
119710092002Enlargement of secretory vesicles by protein tyrosine phosphatase PTP-MEG2 in rat basophilic leukemia mast cells and Jurkat T cells.Wang X et al
163308172005Tyrosine phosphatase MEG2 modulates murine development and platelet and lymphocyte activation through secretory vesicle function.Wang Y et al
129200262003PTP-MEG2 is activated in polycythemia vera erythroid progenitor cells and is required for growth and expansion of erythroid cells.Xu MJ et al
203351742010Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells.Yuan T et al
276559142016The Protein Tyrosine Phosphatase MEG2 Regulates the Transport and Signal Transduction of Tropomyosin Receptor Kinase A.Zhang D et al
230751152012A highly selective and potent PTP-MEG2 inhibitor with therapeutic potential for type 2 diabetes.Zhang S et al
127027262003Specific interaction of protein tyrosine phosphatase-MEG2 with phosphatidylserine.Zhao R et al

Other Information

Locus ID:

NCBI: 5780
MIM: 600768
HGNC: 9661
Ensembl: ENSG00000169410

Variants:

dbSNP: 5780
ClinVar: 5780
TCGA: ENSG00000169410
COSMIC: PTPN9

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000169410ENST00000306726A0A0A0MR09
ENSG00000169410ENST00000561731H3BQT6
ENSG00000169410ENST00000618819P43378

Expression (GTEx)

0
5
10
15
20
25
30

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
153225542004Control of vesicle fusion by a tyrosine phosphatase.37
203351742010Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells.29
278571772016miR-96 promotes cell proliferation, migration and invasion by targeting PTPN9 in breast cancer.26
223946842012Protein tyrosine phosphatase Meg2 dephosphorylates signal transducer and activator of transcription 3 and suppresses tumor growth in breast cancer.25
166792942006Identification of the tyrosine phosphatase PTP-MEG2 as an antagonist of hepatic insulin signaling.21
129200262003PTP-MEG2 is activated in polycythemia vera erythroid progenitor cells and is required for growth and expansion of erythroid cells.19
262882492015Variability of Gene Expression Identifies Transcriptional Regulators of Early Human Embryonic Development.17
287471842017MEG2 is regulated by miR-181a-5p and functions as a tumour suppressor gene to suppress the proliferation and migration of gastric cancer cells.13
146628692003Homotypic secretory vesicle fusion induced by the protein tyrosine phosphatase MEG2 depends on polyphosphoinositides in T cells.12
173871802007Association of protein-tyrosine phosphatase MEG2 via its Sec14p homology domain with vesicle-trafficking proteins.12

Citation

Barnabas Nyesiga ; Anette Gjörloff Wingren

PTPN9 (protein tyrosine phosphatase, non-receptor type 9)

Atlas Genet Cytogenet Oncol Haematol. 2016-11-01

Online version: http://atlasgeneticsoncology.org/gene/41922/ptpn9