Difference between revisions of "Phosphatase Subfamily PTPN6"

Revision as of 19:27, 29 June 2015

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

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 (SHP-2) has a carboxy-terminal immunoreceptor tyrosine-based activation motif (ITAM) [2].

The longest isoform of Drosophila genus do not have the first SH2 domain.

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. [3, 4]) 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) [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 (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 [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 caustic gene of Noonan syndrome phenotype.

PTPN11 (SHP-2) can operat 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].

References

1. Error fetching PMID 16084691: [Poole05]
2. Error fetching PMID 25915733: [Deng15]
3. Error fetching PMID 12826400: [Neel03]
4. Error fetching PMID 19290938: [Lorenz09]
5. Error fetching PMID 25790452: [Xiao15]
6. Error fetching PMID 25876760: [Cerny15]
7. Error fetching PMID 25687756: [Gumbleton15]
8. Error fetching PMID 25802336: [Burmeister15]
9. Error fetching PMID 25100060: [Perino14]
10. Error fetching PMID 24891296: [Edwards14]