Disease relevance of PTPN12

• We have expressed PTP-PEST using recombinant baculovirus, and purified the protein essentially to homogeneity in order to investigate phosphorylation as a potential mechanism of regulation of the enzyme [1].
• Stimulation of human rhabdomyosarcoma A204 cells, a transformed muscle line, with insulin led to an approximately 4-fold induction of PTP-PEST mRNA within 36 h [2].
• Chromosomal localization of the protein tyrosine phosphatase G1 gene and characterization of the aberrant transcripts in human colon cancer cells [3].
• Experiments with an inhibitor to phosphatase and small interference RNA to PTP-PEST confirmed the involvement of PTP-PEST in sealing ring formation and bone resorption [4].
• PTP-PEST, a ubiquitously expressed cytoplasmic tyrosine phosphatase, is thought to play an important role in cell adhesion and motility, and may be involved in metastasis [5].

High impact information on PTPN12

• Herein, we show that the cytosolic protein tyrosine phosphatase PTP-PEST is expressed abundantly in a wide variety of haemopoietic cell types, including B cells and T cells [6].
• Overexpression studies, antisense experiments and structure-function analyses provided evidence that PTP-PEST is an efficient negative regulator of lymphocyte activation [6].
• 3 h after plating on fibronectin, the number and size of vinculin containing focal adhesions were greatly increased in the homozygous PTP-PEST mutant cells as compared with heterozygous cells [7].
• PTP-PEST: a protein tyrosine phosphatase regulated by serine phosphorylation [1].
• PTP-PEST is also phosphorylated on both Ser39 and Ser435 following treatment of intact HeLa cells with TPA, forskolin or isobutyl methyl xanthine (IBMX) [1].

Biological context of PTPN12

• Tyrosine phosphorylation of paxillin, which is greatly enhanced by CAKbeta overexpression, was dramatically reduced upon coexpression of PTP-PEST [8].
• Our results suggest that both PKC and PKA are capable of phosphorylating, and therefore inhibiting, PTP-PEST in vivo, offering a mechanism whereby signal transduction pathways acting through either PKA or PKC may directly influence cellular processes involving reversible tyrosine phosphorylation [1].
• We have investigated the substrate specificity of PTP-PEST by a novel substrate-trapping approach in combination with in vitro dephosphorylation experiments [9].
• The PTP-PEST binding site on paxillin has been mapped to the two carboxyl-terminal LIM (lin11, isl-1, and mec-3) domains [10].
• Roles for the tubulin- and PTP-PEST-binding paxillin LIM domains in cell adhesion and motility [11].

Anatomical context of PTPN12

• Finally, endogenous PTP-PEST and endogenous CAKbeta were found to localize to similar cellular compartments in epithelial and smooth muscle cells [8].
• This exclusive association was observed in lysates from several cell lines and in transfected COS cells, but was not observed with other members of the PTP family, strongly suggesting that p130(cas) represents a major physiologically relevant substrate for PTP-PEST [9].
• Thus, we propose that PTP-PEST, by a competition with the ligand of paxillin in the focal adhesion complex, could contribute to the removal of paxillin from the adhesion sites and consequently promote focal adhesion turnover [12].
• When plated on fibronectin, PTP-PEST (-/-) fibroblasts display a strong defect in motility [7].
• The protein tyrosine phosphatase PEST (PTP-PEST) is involved in the regulation of the actin cytoskeleton [13].

Associations of PTPN12 with chemical compounds

• Both the major autophosphorylation site of CAKbeta (Tyr(402)) and activation loop tyrosine residues, Tyr(579) and Tyr(580), were targeted for dephosphorylation by PTP-PEST [8].
• PTP-PEST is phosphorylated in vitro by both cyclic AMP-dependent protein kinase (PKA) and protein kinase C (PKC) at two major sites, which we have identified as Ser39 and Ser435 [1].
• Expression of PTP-PEST also caused a reduction of phosphotyrosine on paxillin [10].
• Similarly, interaction of the same signaling proteins, as well as PTP-PEST, was observed with glutathione S-transferase-fused proline-rich regions of WASP [4].
• These data provide mechanistic insight into how the paxillin-PTP-PEST interaction contributes to integrin signaling events associated with the spatiotemporal regulation of key modulators of the cytoskeleton and cell motility machinery [14].

Physical interactions of PTPN12

• Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder [15].

Enzymatic interactions of PTPN12

• Mutation of proline 337 within this sequence to alanine significantly impairs the ability of PTP-PEST to recognise tyrosine phosphorylated p130cas as a substrate, without qualitatively affecting the selectivity of the interaction [16].

Regulatory relationships of PTPN12

• Further, PTP-PEST can negatively regulate CAKbeta signaling by inhibiting the catalytic activity of the kinase [8].
• Moreover, we demonstrate that the activities of VAV2 and p190RhoGAP are regulated by PTP-PEST [17].

Other interactions of PTPN12

• Furthermore, PPARgamma agonists induced expression of protein tyrosine phosphatase-PEST (PTP-PEST), and of phosphatase and tensin homologue deleted on chromosome ten (PTEN) [18].
• We demonstrate that a proline-rich segment of PTP-PEST (Pro 2), 355PPEPHPVPPILTPSPPSAFP374, is essential for this interaction in vivo [12].
• A novel PTPase, which we term PTP-PEST, was detected by this method [2].
• These results suggest a role for PTP-PEST in G protein receptor signaling and in cross-talk between G protein receptor and tyrosine kinase receptor pathways [19].
• In order to investigate the abnormality of the PTPG1 transcript in various human cancer cell lines, we have analyzed the consensus catalytic region of PTPG1 cDNA, using the reverse transcription polymerase chain reaction [3].

Analytical, diagnostic and therapeutic context of PTPN12

• Yeast two-hybrid assays demonstrate severely reduced binding between PTP PEST and both the E250Q and A230T mutant proteins [15].
• Northern blot analysis of PTPG1 mRNA showed a 4.6-kb transcript that was detected in a wide variety of cell lines to suggest its extensive expression [20].
• We have cloned and characterized a human cDNA encoding a new member of the family of cytosolic type protein-tyrosine-phosphatase (PTP), designated as PTPG1, from an adult colon tissue cDNA library by using the PCR product as probe [20].
• Combination of gene targeting and substrate trapping to identify substrates of protein tyrosine phosphatases using PTP-PEST as a model [21].
• A MspI polymorphism and linkage mapping of the human protein-tyrosine phosphatase G (PTPRG) gene [22].

References