The rat tyrosine phosphatase eta activates c-src to increase cell-substratum adhesion through FAK and paxillin tyrosine phosphorylation: possible implications in human carcinogenesis

The expression of the receptor protein tyrosine phosphatase r-PTP eta is drastically reduced in rat and human malignant thyroid cells, whereas its restoration reverts the neoplastic phenotype of retrovirally transformed rat thyroid cells. Moreover, reduced levels and loss of heterozygosity of DEP-1, the human homolog of r-PTP eta, have been found in many human neoplasias. Here, we report that the r-PTP eta protein binds to c-Src in living cells and dephosphorylates the c-Src inhibitory tyrosine phosphorylation site (Tyr 529), thereby increasing c-Src tyrosine kinase activity in malignant rat thyroid cells stably transfected with r-PTP eta. Tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin was enhanced in r-PTP eta-expressing cells. This was associated with increased adhesion of malignant r-PTP eta-transfected thyroid cells vs both untransfected cells and cells stably transfected with an inactive r-PTP eta mutant. Treatment of rat thyroid cells with the c-Src inhibitor PP2 decreased cell adhesion to a higher extent in r-PTP eta-transfected cells than in mock-transfected or stably transfected cells with the inactive r-PTP eta mutant, indicating that r-PTP eta regulates cell - substratum adhesion by activating c-Src. Interestingly, the extent of both c-Src dephosphorylation at Tyr 529, FAK and paxillin phosphorylation, and the increased cell adhesion were associated with the degree of r-PTP eta expression