Physical and functional interactions between protein tyrosine phosphatase alpha, PI 3-kinase, and PKCdelta.
The somatostatin analogue, TT-232 inhibits cell proliferation and induces apoptosis in a variety of tumor cells both in vivo and in vitro. While the early transient activation of Erk/MAPK was found to be important for the induction of cell cycle arrest, the signaling pathway leading to the activation of Erk/MAPK had not been fully established. Here we present evidence that activation of the Erk/MAPK pathway by TT-232 involves PI 3-kinase, PKCdelta and the protein tyrosine phosphatase alpha (PTPalpha). We show a physical interaction of PI 3-kinase and PKCdelta with PTPalpha and show that the tyrosine phosphatase plays a role in the activation of MAPK. In this process, PTPalpha Ser-180 and Ser-204 phosphorylation is critical for the induction of phosphatase activity, which is required for dephosphorylation of pp60(c-src). Taken together, we demonstrate the physical and functional association between PI 3-kinase, PKCdelta and PTPalpha in a signaling complex that mediates the antitumor activity of the somatostatin analogue TT-232.
Steták
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A
Department of Medical Chemistry, Peptide Biochemistry Research Group, Semmelweis University, Budapest, H-1088, Hungary. stetak@hotmail.com
Csermely
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P
Ullrich
A
A
Kéri
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019556:COS Cells; D002478:Cells, Cultured; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000502:physiology; D016391:Genes, src / Q000502:physiology; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D016601:RNA-Binding Proteins; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013004:Somatostatin / Q000031:analogs & derivatives; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000970:Antineoplastic Agents; C116747:HNRNPH2 protein, human; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; D007527:Isoenzymes; D010456:Peptides, Cyclic; D016601:RNA-Binding Proteins; D010566:Virulence Factors, Bordetella; D012694:Serine; C094462:TT2-32; D013004:Somatostatin; D019869:Phosphatidylinositol 3-Kinases; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases; D019204:GTP-Binding Proteins