Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells.
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.
van Dijk
T B
TB
Institute of Hematology, Erasmus University Rotterdam, Rotterdam, The Netherlands. vandijk@hema.fgg.eur.nl
van Den Akker
E
E
Amelsvoort
M P
MP
Mano
H
H
Löwenberg
B
B
von Lindern
M
M
D015153:Blotting, Western; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000494:pharmacology*; D010750:Phosphoproteins / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011233:Precipitin Tests; D011485:Protein Binding / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000187:drug effects* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019089:Stem Cell Factor / Q000494:pharmacology*; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D018909:src Homology Domains; D019061:src-Family Kinases / Q000187:drug effects* / Q000378:metabolism
D010750:Phosphoproteins; D019089:Stem Cell Factor; D019869:Phosphatidylinositol 3-Kinases; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases