Eph receptors are negatively controlled by protein tyrosine phosphatase receptor type O

Abstract

Eph receptors are activated by the autophosphorylation of tyrosine residues upon the binding of their ligands, the ephrins; however, the protein tyrosine phosphatases (PTPs) responsible for the negative regulation of Eph receptors have not been elucidated. Here, we identified protein tyrosine phosphatase receptor type O (Ptpro) as a specific PTP that efficiently dephosphorylates both EphA and EphB receptors as substrates. Biochemical analyses revealed that Ptpro dephosphorylates a phosphotyrosine residue conserved in the juxtamembrane region, which is required for the activation and signal transmission of Eph receptors. Ptpro thus seems to moderate the amount of maximal activation of Eph receptors. Using the chick retinotectal projection system, we show that Ptpro controls the sensitivity of retinal axons to ephrins and thereby has a crucial role in the establishment of topographic projections. Our findings explain the molecular mechanism that determines the threshold of the response of Eph receptors to ephrins in vivo.

Substrate Specificity of R3 Receptor-like Protein-tyrosine Phosphatase Subfamily toward Receptor Protein-tyrosine Kinases

“…Analyses of double or triple mutant mice should thus reveal the physiological roles of R3 RPTPs. We previously reported that chick Ptprj cannot dephosphorylate Eph receptors (6). This difference may be attributable to a species difference: the amino acid sequences of the ICR of mouse Ptprj and chick Ptprj have only 78% identity, whereas those of Ptpro have 93% identity.…”

“…Previously we identified substrates for Ptpro (with a single PTP domain) (6) and Ptprz (with tandem PTP domains) (18,19) by using a two-hybrid system with substrate-trapping RPTP mutants. In this study, we expanded the screening to include almost the entire RPTK family to find substrates for the R3 RPTP subfamily by using mammalian cDNA clones.…”

“…by Mammalian Two-hybrid Assays-To examine the enzymesubstrate interaction between RPTPs and RPTKs, we took advantage of mammalian two-hybrid assays with substratetrapping mutants of PTPs (6). The respective DA mutant in which the general aspartic acid (D) residue in the PTP domain is converted to alanine (A) retains the ability to recognize and bind substrates stably although the phosphatase activity is lost (Fig.…”

“…For example, we have shown that Ptpro plays an important role in axonal navigation through the regulation of Eph receptors (6). In addition, Ptprz dephosphorylates ErbB4 and TrkA as physiological substrates (7,8).…”

GLEPP1/Protein-tyrosine Phosphatase ϕ Inhibitors Block Chemotaxis in Vitro and in Vivo and Improve Murine Ulcerative Colitis

“…(i) Using EphA and -B receptors as substrate, GLEPP1 plays a role in axonal guidance (25,26). (ii) GLEPP/PTPRO was characterized as a tumor suppressor gene, with CpG island promoter hypermethylation and reduced expression seen in primary tumors and tumor cell lines (27)(28)(29).…”