Difference between revisions of "Phosphatase Subfamily PTPRA"

Revision as of 21:36, 19 February 2015

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. Error fetching PMID 12861030: [elson03]
2. Error fetching PMID 12193229: [Wabakken]
3. Error fetching PMID 17212655: [kapp07]
4. Error fetching PMID 15845350: [roskoski05]
5. Error fetching PMID 15522235: [nakagawa04]
6. Error fetching PMID 7518772: [hertog94]
7. Error fetching PMID 10490839: [elson99]
8. Error fetching PMID 18093973: [elson08]
9. Error fetching PMID 10859312: [tanuma00]
10. Error fetching PMID 12615930: [elson03b]