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, 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 [1].
The second phosphatase domain mediates the dimerization, which regulates the catalytic activity [2].
Functions
Human PTPRA and PTPRE are candidate phosphatases of Src kinases [3, 4].
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 [5].
References
- 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 |
- 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 |
- 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 |
- 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 |
- 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 |
