Phosphatase Subfamily PTPN6

Phosphatase Classification: Fold CC1:Superfamily CC1: Family PTP: Subfamily PTPN6 (SHP/SHIP/csw/Corkscrew)

Evolution

The PTPN6 subfamily is found across holozoa. It is a single copy in most invertebrate genomes and two or three copies in most vertebrates. Human has two members, PTPN6 (SHP1) and PTPN11 (SHP2).

Domain

The PTPN6 subfamily has two tandem SH2 domains and phosphatase domain. Besides the structural domains, it has a C-terminal tail important for the regulation of its function [1]. For example, PTPN11 (SHP2) has a carboxy-terminal immunoreceptor tyrosine-based activation motif (ITAM) [2].

The genes of PTPN6 subfamily have multiple alternative splicing isoforms, which may result in different domain combinations. For instance, the longest isoform of Drosophila genus do not have the first SH2 domain (technical notes: the longest isoforms in Ensembl genomes).

Functions

Human PTPN6 (SHP1) and PTPN11 (SHP2) are proposed to have different roles in signal transduction: PTPN6 plays a largely negative signalling role, whereas PTPN11 plays a largely positive role in cell signalling leading to cell activation. Expression of PTPN6 is restricted mainly to haematopoietic cells whereas PTPN11 is more widely expressed; both enzymes are expressed in many haematopoietic cells [1].

The PTPN6 subfamiy is extensively studied and reviewed (e.g. [3, 4]). Below are some examples of their functions:

PTPN6/SHP1

PTPN6/SHP-1 dephosphorylates and inhibites Transient receptor potential vanilloid 1 (TRPV1) receptors in rat dorsal root ganglions (DRGs) [5]. TRPV1 is a nonselective cation channel that provides sensation of scalding heat and pain (nociception).

The bacterial pathogen Bordetella pertussis can hijack PTPN6 (SHP-1) by the adenylate cyclase toxin-hemolysin (CyaA). CyaA penetrates complement receptor 3-expressing phagocytes and catalyzes uncontrolled conversion of cytosolic ATP to the key second messenger molecule cAMP. CyaA/cAMP signaling induced SHP phosphatase-dependent dephosphorylation of the c-Fos subunit of the transcription factor AP-1, therefore inhibiting TLR4-triggered induction of iNOS gene expression and suppressing production of bactericidal NO in macrophage cells [6].

PTPN6 expression by NK cells is required for in vivo-mismatched bone marrow allograft rejection as well as for NK memory responses to happen [7].

PTPN11/SHP2

PTPN11 is a major player in receptor tyrosine kinase signaling to Ras, by a variety of mechanisms.

PKA phosphorylates PTPN11/SHP-2 at Thr-73 and Ser-189 in two SH2 domains, respectively. The phosphorylation inhibits ligand-binding mediated by SH2 domains and phosphatase activity [8].

PTPN11/SHP-2 acts as a regulator of the tyrosyl phosphorylation of FGFR4 and of its immediate target FRS2α, thus being essential for the FGF15/19-mediated activation of the FGFR4/P-ERK1/2/PKC signaling pathway as a integrator of hepatic bile acid and FGF15/FGF19 signaling [9].

A PTPN11 allele encoding a catalytically impaired protein was found in a patient with a Noonan syndrome phenotype [10]. But, it is unclear whether PTPN11 is a general casuative gene of Noonan syndrome.

PTPN11 (SHP-2) can operate as a scaffold, facilitating the recruitment of kinase Syk to the CLR dectin-1 or the adaptor FcRγ, through its N-SH2 domain and a carboxy-terminal immunoreceptor tyrosine-based activation motif (ITAM) [2].

PTPN11 (SHP-2) promotes liver cancer stem cell expansion by augmenting β-catenin signaling and predicts chemotherapeutic response of patients [11].

Drosophila Corkscrew (csw)

Drosophila has a single gene of PTPN6 subfamily, corkscrew (csw). It binds to and dephosphorylates Draper-II, an alternative splice variant of Draper [12], which is orthologous to human MEGF11 (multiple EGF-like-domains 11).

References

1. Poole AW and Jones ML. A SHPing tale: perspectives on the regulation of SHP-1 and SHP-2 tyrosine phosphatases by the C-terminal tail. Cell Signal. 2005 Nov;17(11):1323-32. DOI:10.1016/j.cellsig.2005.05.016 |
2. Deng Z, Ma S, Zhou H, Zang A, Fang Y, Li T, Shi H, Liu M, Du M, Taylor PR, Zhu HH, Chen J, Meng G, Li F, Chen C, Zhang Y, Jia XM, Lin X, Zhang X, Pearlman E, Li X, Feng GS, and Xiao H. Tyrosine phosphatase SHP-2 mediates C-type lectin receptor-induced activation of the kinase Syk and anti-fungal TH17 responses. Nat Immunol. 2015 Jun;16(6):642-52. DOI:10.1038/ni.3155 |
3. Neel BG, Gu H, and Pao L. The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci. 2003 Jun;28(6):284-93. DOI:10.1016/S0968-0004(03)00091-4 |
4. Lorenz U. SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels. Immunol Rev. 2009 Mar;228(1):342-59. DOI:10.1111/j.1600-065X.2008.00760.x |
5. Xiao X, Zhao XT, Xu LC, Yue LP, Liu FY, Cai J, Liao FF, Kong JG, Xing GG, Yi M, and Wan Y. Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats. Pain. 2015 Apr;156(4):597-608. DOI:10.1097/01.j.pain.0000460351.30707.c4 |
6. Cerny O, Kamanova J, Masin J, Bibova I, Skopova K, and Sebo P. Bordetella pertussis Adenylate Cyclase Toxin Blocks Induction of Bactericidal Nitric Oxide in Macrophages through cAMP-Dependent Activation of the SHP-1 Phosphatase. J Immunol. 2015 May 15;194(10):4901-13. DOI:10.4049/jimmunol.1402941 |
7. Gumbleton M, Vivier E, and Kerr WG. SHIP1 intrinsically regulates NK cell signaling and education, resulting in tolerance of an MHC class I-mismatched bone marrow graft in mice. J Immunol. 2015 Mar 15;194(6):2847-54. DOI:10.4049/jimmunol.1402930 |
8. Burmeister BT, Wang L, Gold MG, Skidgel RA, O'Bryan JP, and Carnegie GK. Protein Kinase A (PKA) Phosphorylation of Shp2 Protein Inhibits Its Phosphatase Activity and Modulates Ligand Specificity. J Biol Chem. 2015 May 8;290(19):12058-67. DOI:10.1074/jbc.M115.642983 |
9. Perino A and Schoonjans K. Another Shp on the horizon for bile acids. Cell Metab. 2014 Aug 5;20(2):203-5. DOI:10.1016/j.cmet.2014.07.019 |
10. Edwards JJ, Martinelli S, Pannone L, Lo IF, Shi L, Edelmann L, Tartaglia M, Luk HM, and Gelb BD. A PTPN11 allele encoding a catalytically impaired SHP2 protein in a patient with a Noonan syndrome phenotype. Am J Med Genet A. 2014 Sep;164A(9):2351-5. DOI:10.1002/ajmg.a.36620 |
11. Xiang D, Cheng Z, Liu H, Wang X, Han T, Sun W, Li X, Yang W, Chen C, Xia M, Liu N, Yin S, Jin G, Lee T, Dong L, Hu H, Wang H, and Ding J. Shp2 promotes liver cancer stem cell expansion by augmenting β-catenin signaling and predicts chemotherapeutic response of patients. Hepatology. 2017 May;65(5):1566-1580. DOI:10.1002/hep.28919 |
12. Logan MA, Hackett R, Doherty J, Sheehan A, Speese SD, and Freeman MR. Negative regulation of glial engulfment activity by Draper terminates glial responses to axon injury. Nat Neurosci. 2012 Mar 18;15(5):722-30. DOI:10.1038/nn.3066 |