The protein-tyrosine phosphatase TCPTP regulates epidermal growth factor receptor-mediated and phosphatidylinositol 3-kinase-dependent signaling

In this study we have investigated the down-regulation of epidermal growth factor (EGF) receptor signaling by protein-tyrosine phosphatases (PTPs) in COS1 cells. The 45-kDa variant of the PTP TCPTP (TC45) exits the nucleus up on EGF receptor activation and recognizes the EGF receptor as a cellular su bstrate. We report that TC45 inhibits the EGF-dependent activation of the c -Jun N-terminal kinase, but does not alter the activation of extracellular signal-regulated kinase 2. These data demonstrate that TC45 can regulate se lectively mitogen-activated protein kinase signaling pathways emanating fro m the EGF receptor. In EGF receptor-mediated signaling, the protein kinase PKB/Akt and the mitogen-activated protein kinase c-Jun N-terminal kinase, b ut not extracellular signal-regulated kinase 2, function downstream of phos phatidylinositol 3-kinase (PI 3-kinase). We have found that TC45 and the TC 45-D182A mutant, which is capable of forming stable complexes with TC45 sub strates, inhibit almost completely the EGF-dependent activation of PI 3-kin ase and PKB/Akt. TC45 and TC45-D182A act upstream of PI 3-kinase, most like ly by inhibiting the recruitment of the p85 regulatory subunit of PI 3-kina se by the EGF receptor. Recent studies have indicated that the EGF receptor can be activated in the absence of EGF following integrin ligation. We fin d that the integrin-mediated activation of PKB/Akt in COS1 cells is abrogat ed by the specific EGF receptor protein-tyrosine kinase inhibitor tyrphosti n AG1478, and that TC45 and TC45-D182A can inhibit activation of PKB/Akt fo llowing the attachment of COS1 cells to fibronectin. Thus, TC45 may serve a s a negative regulator of growth factor or integrin-induced, EGF receptor-m ediated PI 3-kinase signaling.