The phosphatidylinositol 3' kinase pathway is required for the survival signal of leukocyte tyrosine kinase.

Leukocyte tyrosine kinase (LTK) is a receptor tyrosine kinase which belongs to the insulin receptor superfamily and is mainly expressed in pre-B lymphocytes and neuronal tissues. Recently, we demonstrated that LTK utilizes Shc and IRS-1 as two major substrates and while both equally activate the Ras pathway, only IRS-1 suppresses ...
apoptosis of hematopoietic cells, suggesting the existence of another unidentified signaling pathway downstream of IRS-1, which is relevant to the anti-apoptotic activity. In the present study, we found that wortmannin, a specific inhibitor of phosphatidylinositol 3' (PI3)-kinase, abolished the survival effects of LTK. Although c-Cbl is found to be phosphorylated by LTK and therefore is a second candidate linking LTK with the PI3-kinase pathway along with IRS-1, we found that the p85 subunit of PI3 kinase directly binds to tyrosine 753 of LTK, which is located within a YXXM motif, a consensus binding amino acid sequence for the SH2 domain of p85, but fails to bind to IRS-1 or c-Cbl. Ba/F3 cells which stably express the EGF receptor-LTK chimeric receptor carrying a mutation at tyrosine 753 fell into apoptotic death even in the presence of EGF, indicating that the PI3 kinase pathway is required for the survival effects of LTK.
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, Androstadienes, Animals, Apoptosis, Binding Sites, Cell Line, Cell Survival, Enzyme Inhibitors, Humans, Mice, Mutation, Phosphoproteins, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Receptor Protein-Tyrosine Kinases, Signal Transduction, Tyrosine, Ubiquitin-Protein Ligases
Oncogene
Date: Jun. 26, 1997
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