Phosphatase Subfamily PTPN9

Phosphatase Classification: Fold CC1:Superfamily CC1: Family PTP: Subfamily PTPN9 (MEG2/PTPMEG2)

PTPN9 (MEG2) is a non-receptor tyrosine phosphatase involved in vesicle fusion in the secretory pathway.

Evolution

PTPN9 emerged is found in animals, usually as a single copy. It is absent from nematodes

Domain

PTPN9 has two domains: a N-terminal domain homologous to yeast Sec14p and a C-terminal phosphatase domain [1].

The N-terminal Sec14p homology domain localizes the protein to secretory vesicles, by binding to phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P(3)) on secretory vesicle membranes [2] and/or mannose 6-phosphate receptor-interacting protein TIP47 and Arfaptin2 on vesicles [3].

Functions

PTPN9 is widely expressed in different tissues [1] (also see GTEx).

PTPN9 plays important role in regulated secretion. It localizes to secretory vesicle membranes through its N-terminal Sec14p homolog domain binding to phosphatidylinositol-3,4,5-trisphosphate [2] and/or mannose 6-phosphate receptor-interacting protein TIP47 and Arfaptin2 on vesicles [3]. It induces homotypic secretory vesicle fusion. It dephosphorylates N-ethylmaleimide-sensitive factor (NSF), a key regulator of vesicle fusion, at Tyr 83, which resulted in the local release of NSF from a tyrosine-phosphorylated, inactive state [4].

PTPN9 localizes to secondary and tertiary granules and secretory vesicles in neutrophils, and may regulate phagocytosis, an essential antimicrobial function in the innate immune response [5], and is involved in the development of erythroid cells [6].

PTPN9 directly interacts with STAT3 and mediates its dephosphorylation in the cytoplasm [7].

PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells [8], and vascular endothelial growth factor receptor (perhaps on Tyr-1175) in endothelial cells [9].

The human gene is implicated in signaling between insulin receptor (InsR) and the FoxO transcription factor [10].

References

1. Gu M, Warshawsky I, and Majerus PW. Cloning and expression of a cytosolic megakaryocyte protein-tyrosine-phosphatase with sequence homology to retinaldehyde-binding protein and yeast SEC14p. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2980-4. DOI:10.1073/pnas.89.7.2980 |
2. Huynh H, Wang X, Li W, Bottini N, Williams S, Nika K, Ishihara H, Godzik A, and Mustelin T. Homotypic secretory vesicle fusion induced by the protein tyrosine phosphatase MEG2 depends on polyphosphoinositides in T cells. J Immunol. 2003 Dec 15;171(12):6661-71. DOI:10.4049/jimmunol.171.12.6661 |
3. Saito K, Williams S, Bulankina A, Höning S, and Mustelin T. Association of protein-tyrosine phosphatase MEG2 via its Sec14p homology domain with vesicle-trafficking proteins. J Biol Chem. 2007 May 18;282(20):15170-8. DOI:10.1074/jbc.M608682200 |
4. Huynh H, Bottini N, Williams S, Cherepanov V, Musumeci L, Saito K, Bruckner S, Vachon E, Wang X, Kruger J, Chow CW, Pellecchia M, Monosov E, Greer PA, Trimble W, Downey GP, and Mustelin T. Control of vesicle fusion by a tyrosine phosphatase. Nat Cell Biol. 2004 Sep;6(9):831-9. DOI:10.1038/ncb1164 |
5. Kruger JM, Fukushima T, Cherepanov V, Borregaard N, Loeve C, Shek C, Sharma K, Tanswell AK, Chow CW, and Downey GP. Protein-tyrosine phosphatase MEG2 is expressed by human neutrophils. Localization to the phagosome and activation by polyphosphoinositides. J Biol Chem. 2002 Jan 25;277(4):2620-8. DOI:10.1074/jbc.M104550200 |
6. Xu MJ, Sui X, Zhao R, Dai C, Krantz SB, and Zhao ZJ. PTP-MEG2 is activated in polycythemia vera erythroid progenitor cells and is required for growth and expansion of erythroid cells. Blood. 2003 Dec 15;102(13):4354-60. DOI:10.1182/blood-2003-04-1308 |
7. Su F, Ren F, Rong Y, Wang Y, Geng Y, Wang Y, Feng M, Ju Y, Li Y, Zhao ZJ, Meng K, and Chang Z. Protein tyrosine phosphatase Meg2 dephosphorylates signal transducer and activator of transcription 3 and suppresses tumor growth in breast cancer. Breast Cancer Res. 2012 Mar 6;14(2):R38. DOI:10.1186/bcr3134 |
8. Yuan T, Wang Y, Zhao ZJ, and Gu H. Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells. J Biol Chem. 2010 May 14;285(20):14861-14870. DOI:10.1074/jbc.M109.099879 |
9. Hao Q, Samten B, Ji HL, Zhao ZJ, and Tang H. Tyrosine phosphatase PTP-MEG2 negatively regulates vascular endothelial growth factor receptor signaling and function in endothelial cells. Am J Physiol Cell Physiol. 2012 Sep 1;303(5):C548-53. DOI:10.1152/ajpcell.00415.2011 |
10. Cho CY, Koo SH, Wang Y, Callaway S, Hedrick S, Mak PA, Orth AP, Peters EC, Saez E, Montminy M, Schultz PG, and Chanda SK. Identification of the tyrosine phosphatase PTP-MEG2 as an antagonist of hepatic insulin signaling. Cell Metab. 2006 May;3(5):367-78. DOI:10.1016/j.cmet.2006.03.006 |