Difference between revisions of "Phosphatase Subfamily PTPN6"

Revision as of 17:14, 22 April 2015

Phosphatase Classification: Fold CC1:Superfamily CC1: Family PTP: Subfamily PTPN6 (SHP)

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].

Functions

Human PTPN6 (SHP-1) and PTPN11 (SHP-2) are proposed to have different roles in signal transduction: PTPN6/SHP-1 plays a largely negative signalling role, whereas PTPN11/SHP-2 plays a largely positive role in cell signalling leading to cell activation. Expression of PTPN6/SHP-1 is restricted mainly to haematopoietic cells whereas PTPN11/SHP-2 is more widely expressed; both enzymes are expressed in many haematopoietic cells [1].

The PTPN6/SHP subfamiy is under extensive studies and see more in reviews (e.g. [2, 3]) and papers. Below are some examples of their functions:

PTPN6 (SHP-1)

PTPN6/SHP-1 dephosphorylates and inhibites Transient receptor potential vanilloid 1 (TRPV1) receptors in rat dorsal root ganglions (DRGs) [4]. 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 [5].

PTPN11 (SHP-2)

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 [6].

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 [7].

A PTPN11 allele encoding a catalytically impaired protein was found in a patient with a Noonan syndrome phenotype [8]. But, it is unclear whether PTPN11 is a general caustic gene of Noonan syndrome phenotype.

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 | PubMed ID:16084691 | HubMed [Poole05]
2. 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 | PubMed ID:12826400 | HubMed [Neel03]
3. 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 | PubMed ID:19290938 | HubMed [Lorenz09]
4. 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 | PubMed ID:25790452 | HubMed [Xiao15]
5. 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 | PubMed ID:25876760 | HubMed [Cerny15]
6. 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 | PubMed ID:25802336 | HubMed [Burmeister15]
7. 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 | PubMed ID:25100060 | HubMed [Perino14]
8. 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 | PubMed ID:24891296 | HubMed [Edwards14]