Phosphatase Subfamily PTPRA

Phosphatase Classification: Superfamily CC1: Family PTP: Subfamily PTPRA

PTPRA is a deuterostome-specific receptor PTP subfamily

Evolution

PTPRA and PTPRE are related human genes with homologs across vertebrates. No conclusive invertebrate homologs have been found, though the phosphatase domains are most similar to the invertebrate Ptp69D subfamily. Phosphatase fragments in Branchiostoma, Ciona and Urchin are most similar to vertebrate PTPRA and may well be orthologous. The Ciona gene has a long array of Sushi, mucin and ricin domains on the extracellular region, and the other two are fragments lacking the putative extracellular region. See PTPRA-details.

Domain Structure

All members have twin intracellular PTP phosphatase catalytic domains and a conserved juxtamembrane region of ~90 AA between the transmembrane region and the first PTP domain. Both have short, poorly conserved extracellular regions and neither are known to bind ligand. In human PTPRA, the extracellular region is 132 AA long, has poor conservation even between mammals and fish and low sequence complexity. NCBI CDD annotates it weakly as an endomucin domain, a region found in several surface-expressed endothelial proteins (Pfam: PF07010 [1]). No sequence similarity is seen to any protein other than vertebrate PTPRA.

PTPRE has multiple splice forms [1], including one with an alternative N-terminus that lacks a signal peptide, and one with a 26 AA extracellular region, which is also poorly conserved between vertebrate homologs. The intracellular juxtamembrane region (upstream of the PTP domains) of ~88 AA is highly conserved between vertebrate homologs. An additional splice form of PTPRE has been reported, which replaces the second PTP domain with a unique tail [2].

The second phosphatase domain mediates the dimerization, which regulates the catalytic activity [1].

Functions

Both human PTPRA and PTPRE are candidate phosphatases of Src kinases [3, 4, 5].

Both human PTPRA and PTPRE can interact with SH3-SH2-SH3 adaptor protein GRB2 [6, 7] via the interaction between carboxy-terminal phosphotyrosine and GRB2 (for PTPRE, between pTyr and SH2 domain).

PTPRE can dephosphorylate with adaptor Shc [8]. PTPRE binds Shc in a phosphotyrosine-independent manner mediated by the Shc PTB domain and aided by a sequence of 10 N-terminal residues in PTPRE. The dephosphorylation of Shc in a kinase-dependent manner; PTPRE targets Shc in the presence of Src but not in the presence of Neu (a kinase of EGFR family). Neu protects Shc from dephosphorylation by binding the PTB domain of Shc, most likely competing against PTPRE for binding the same domain.

PTPRE, the non-receptor isoform, dephosphorylates pTyr-124 of a voltage-gated potassium channel Kv2.1 [1].

In mouse, overexpression of PTPRE resulted in lower levels of IL-6-induced tyrosine phosphorylation of Jak1, Tyk2, gp130, and Stat3, which suggested that PTPRE is involved in negative regulation of IL-6- and LIF-induced Jak-STAT signaling [9].

References

1. Toledano-Katchalski H, Tiran Z, Sines T, Shani G, Granot-Attas S, den Hertog J, and Elson A. Dimerization in vivo and inhibition of the nonreceptor form of protein tyrosine phosphatase epsilon. Mol Cell Biol. 2003 Aug;23(15):5460-71. DOI:10.1128/MCB.23.15.5460-5471.2003 |
2. Wabakken T, Hauge H, Funderud S, and Aasheim HC. Characterization, expression and functional aspects of a novel protein tyrosine phosphatase epsilon isoform. Scand J Immunol. 2002 Sep;56(3):276-85. DOI:10.1046/j.1365-3083.2002.01127.x |
3. Kapp K, Siemens J, Weyrich P, Schulz JB, Häring HU, and Lammers R. Extracellular domain splice variants of a transforming protein tyrosine phosphatase alpha mutant differentially activate Src-kinase dependent focus formation. Genes Cells. 2007 Jan;12(1):63-73. DOI:10.1111/j.1365-2443.2006.01034.x |
4. Roskoski R Jr. Src kinase regulation by phosphorylation and dephosphorylation. Biochem Biophys Res Commun. 2005 May 27;331(1):1-14. DOI:10.1016/j.bbrc.2005.03.012 |
5. Nakagawa Y, Yamada N, Shimizu H, Shiota M, Tamura M, Kim-Mitsuyama S, and Miyazaki H. Tyrosine phosphatase epsilonM stimulates migration and survival of porcine aortic endothelial cells by activating c-Src. Biochem Biophys Res Commun. 2004 Dec 3;325(1):314-9. DOI:10.1016/j.bbrc.2004.10.029 |
6. den Hertog J, Tracy S, and Hunter T. Phosphorylation of receptor protein-tyrosine phosphatase alpha on Tyr789, a binding site for the SH3-SH2-SH3 adaptor protein GRB-2 in vivo. EMBO J. 1994 Jul 1;13(13):3020-32. DOI:10.1002/j.1460-2075.1994.tb06601.x |
7. Toledano-Katchalski H and Elson A. The transmembranal and cytoplasmic forms of protein tyrosine phosphatase epsilon physically associate with the adaptor molecule Grb2. Oncogene. 1999 Sep 9;18(36):5024-31. DOI:10.1038/sj.onc.1202883 |
8. Kraut-Cohen J, Muller WJ, and Elson A. Protein-tyrosine phosphatase epsilon regulates Shc signaling in a kinase-specific manner: increasing coherence in tyrosine phosphatase signaling. J Biol Chem. 2008 Feb 22;283(8):4612-21. DOI:10.1074/jbc.M708822200 |
9. Tanuma N, Nakamura K, Shima H, and Kikuchi K. Protein-tyrosine phosphatase PTPepsilon C inhibits Jak-STAT signaling and differentiation induced by interleukin-6 and leukemia inhibitory factor in M1 leukemia cells. J Biol Chem. 2000 Sep 8;275(36):28216-21. DOI:10.1074/jbc.M003661200 |