Stem cell factor (SCF) has an important role in the proliferation, differentiation, survival, and migration of hematopoietic cells. SCF exerts its effects by binding to cKit, a receptor with intrinsic tyrosine kinase activity. Activation of phosphatidylinositol 3'-kinase (PI3-K) by cKit was previously shown to contribute to many SCF-induced cellular responses. Therefore, PI3-K-dependent signaling pathways activated by SCF were investigated. The PI3-K-dependent activation and phosphorylation of the tyrosine kinase Tec and the adapter molecule p62Dok-1 are reported. The study shows that Tec and Dok-1 form a stable complex with Lyn and 2 unidentified phosphoproteins of 56 and 140 kd. Both the Tec homology and the SH2 domain of Tec were identified as being required for the interaction with Dok-1, whereas 2 domains in Dok-1 appeared to mediate the association with Tec. In addition, Tec and Lyn were shown to phosphorylate Dok-1, whereas phosphorylated Dok-1 was demonstrated to bind to the SH2 domains of several signaling molecules activated by SCF, including Abl, CrkL, SHIP, and PLCgamma-1, but not those of Vav and Shc. These findings suggest that p62Dok-1 may function as an important scaffold molecule in cKit-mediated signaling.

1-Phosphatidylinositol 3-Kinase/*pharmacology, Blotting, Western, Erythroid Progenitor Cells/drug effects/metabolism, Hematopoietic Stem Cells/drug effects/enzymology/*metabolism, Humans, Phosphoproteins/*drug effects/metabolism, Phosphorylation/drug effects, Precipitin Tests, Protein Binding/drug effects, Protein-Tyrosine Kinase/*drug effects/metabolism, Proto-Oncogene Proteins c-kit/metabolism, Research Support, Non-U.S. Gov't, Signal Transduction/drug effects, Stem Cell Factor/*pharmacology, Substrate Specificity, Tumor Cells, Cultured, src Homology Domains, src-Family Kinases/*drug effects/metabolism
hdl.handle.net/1765/9530
Blood
Erasmus MC: University Medical Center Rotterdam

van Dijk, T.B, Parren-Van Amelsvoort, M, Mano, H, von Lindern, M.M, Löwenberg, B, & van den Akker, E. (2000). Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells. Blood. Retrieved from http://hdl.handle.net/1765/9530