Difference between revisions of "Phosphatase Subfamily PTPRD"
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Revision as of 17:20, 23 February 2015
Phosphatase Classification: Fold CC1: Superfamily CC1: Family PTP: Subfamily PTPRD
PTPRD (LAR) subfamily consists of three members in human.
Evolution
PTPRD subfamily is found in holozoan (metazoan plus it closest relative choanoflagellate). PTPRD subfamily has three gene members in human and most vertebrates: PTPRD, PTPRF and PTPRS. It has single member in most invertebrate metazoan and is under intensive studies in frtui fly. Interestingly, it greatly expanded in sponge.
Domain Structure
All three members of PTPRD subfamily in human has twin intracellular PTP phosphatase domains, and extracellular Ig domains and FN3 domains. Each of them have multiple alternative splicing isoforms (for example, [1]).
Functions
PTPRF (LAR)
The best characterized member of the three human genes in the subfamily is PTPRF, aka LAR. Knock-down of PTPRF by siRNA induced post-receptor insulin resistance with the insulin-induced activation of PKB/Akt and MAP kinases markedly inhibited. But, the phosphorylation and dephosphorylation of the IR and insulin receptor substrate (IRS) proteins were unaffected by PTPRF knock-down [2].
PTPRF dephosphorylates phosphorylated tyrosine residues in both the COOH terminus and kinase domain of Fyn in vitro. It binds to Fyn Src homology 2 domain when its 2nd phosphatase was tyrosine phosphorylated by Fyn tyrosine kinase. In addition to Fyn kinase, PTPRF mutants, with Cys to Ser mutation in the catalytic center of 1st phosphatase domain, can bind to tyrosine-phosphorylated Lck kinase [3].
PTPRF dephosphorylates Death-associated protein kinase (DAPK) at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK [4]. (Note: Upon EGF stimulation, a rapid Src activation leads to subsequent LAR downregulation.)
PTPRF targets to lipid rafts via the interaction with caveolin-1 [5].
PTPRF plays important roles in cell-cell communication. PTPRF localizes to cadherin-beta-catenin-based cellular junctions. Assembly and disassembly of these junctions are regulated by tyrosine phosphorylation. PTPRF dephosphorylates E-cadherin (epithelial cadherin) in vitro [6]. The ectopic expression of PTPRF inhibits epithelial cell migration by preventing phosphorylation and the increase in the free pool of beta-catenin [7].
PTPRF also specifically dephosphorylates and destabilizes BCAR1/p130Cas (breast cancer anti-estrogen resistance 1) and may play a role in regulating cell adhesion-mediated cell survival [8].
PTPRF is involved in the pathogenesis of insulin resistance by binding and dephosphorylating insulin receptor. Its overexpression in muscle causes insulin resistance [9]. PTPRF associates with and preferentially dephosphorylates the insulin receptor that was tyrosine phosphorylated by insulin stimulation. When replace cysteine residue at catalytic motif with serine at the 1st phosphatase domain, PTPRF fails to dephosphorylate insulin receptor, which indicates 1t domain carries out the activity []. Replacing cysteine with serine at the 2nd domain resulted in weaker association, which suggests the 2nd domain may play regulatory role [10, 11].
PTPRF dephosphorylated EphA2 (ephrin type-A receptor 2) at phosphotyrosyl 930, uncoupling Nck1 from EphA2 and thereby attenuating EphA2-mediated cell migration [12].
PTPRD
Human PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers [13]. PTPRD loss can cause of aberrant STAT3 activation in gliomas [14]. Human PTPRD is also associated with restless legs syndrome [15], but the underlying mechanism is unclear. PTPRD interacts with MIM-B, a putative metastasis suppressor protein binding to actin [16]. It is not clear whether MIM-B is its substrate. The 2nd phosphatase domain of PTPRD can bind to inhibit the 1st phosphatase domain of PTPRS [17].
References
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