View source for Phosphatase Subfamily PTPRA

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[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_PTP|Family PTP]]: [[Phosphatase_Subfamily_PTPRA|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 homolog has been found, though the phosphatase domains are most similar to the invertebrate [[Subfamily_Ptp69D|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. The extracelular region of human PTPRA is 132 AA long, of low sequence complexity and has poor conservation even between mammals and fish. NCBI CDD annotates it weakly as an endomucin domain, a region found in several surface-expressed endothelial proteins (Pfam: PF07010 [http://pfam.xfam.org/family/PF07010]). No sequence similarity is seen to any protein other than vertebrate PTPRA. 

PTPRE has multiple splice forms <cite>elson03</cite>, 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 <cite>Wabakken</cite>. The second phosphatase domain mediates dimerization, which regulates the catalytic activity <cite>elson03</cite>.

===Functions===
Human PTPRA and PTPRE are both candidate [http://kinase.com/wiki/index.php/Kinase_Family_Src Src] kinase phosphatases <cite>kapp07, roskoski05, nakagawa04</cite>. Both can interact with SH3-SH2-SH3 adaptor protein GRB2 <cite>hertog94, elson99</cite> via the interaction between carboxy-terminal phosphotyrosine and GRB2 (for PTPRE, between the pTyr and the SH2 domain).

PTPRE can dephosphorylate the Shc adaptor <cite>elson08</cite>. 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. 

cyt-PTPRE, the non-receptor isoform, dephosphorylates pTyr-124 of the voltage-gated potassium channel Kv2.1, reversing its activation by Src family kinases <cite>elson00, elson03b</cite>.

PTPRE is a negative regulator of insulin receptor (IR) signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver <cite>nakagawa05</cite>.

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 <cite>tanuma00</cite>.

===References===
<biblio>
#Wabakken pmid=12193229
#kapp07 pmid=17212655
#tanuma00 pmid=10859312
#roskoski05 pmid=15845350
#elson99 pmid=10490839
#hertog94 pmid=7518772
#elson00 pmid=10921884
#elson03 pmid=12861030
#elson03b pmid=12615930
#elson08 pmid=18093973
#nakagawa04 pmid=15522235
#nakagawa05 pmid=15738637
</biblio>