Formation of signal transfer complexes between stem cell and platelet-derived growth factor receptors and SH2 domain proteins in vitro.
Cellular growth and differentiation signals are generated and defined by the interaction of specific phosphotyrosine residues of activated receptor tyrosine kinases (RTKs) and src homology-2 (SH2) domain-containing intracellular signal transducers. This appears to involve for both the p145c-kit and beta platelet-derived growth factor receptor (PDGF-R) cytoplasmic domains the formation of multiprotein signal transfer complexes, which include combinations of noncatalytic and enzymatically active subunits of phosphatidylinositol 3'-kinase (PI3'-K), phospholipase C-gamma (PLC gamma), and guanosine trisphosphatase activating protein (GAP). In vitro association experiments indicate that PLC gamma and PI3'-K bind the beta PDGF-R simultaneously, while these two SH2 proteins compete for association to p145c-kit binding sites, with p85/PI3'-K exhibiting higher affinity. Interestingly, GAP and p85/PI3'-K binding to distinct p145c-kit phosphotyrosines is cooperative, enhancing formation of a heterotetrameric signaling complex, which may include different combinations of p85 alpha and p85 beta with p110, p112, and p116 by interaction with the same tyrosine 721 docking site. The diversity of molecular interactions observed for PDGF-R and p145c-kit suggests a new mode of signal definition and modulation.
Herbst
R
R
Department of Molecular Biology, Max-Planck-Institut für Biochemie, Martinsried, Germany.
Shearman
M S
MS
Jallal
B
B
Schlessinger
J
J
Ullrich
A
A
D000595:Amino Acid Sequence; D001483:Base Sequence; D001667:Binding, Competitive; D002460:Cell Line; D004622:Embryo, Mammalian; D020690:GTPase-Activating Proteins; D006801:Humans; D007163:Immunosorbent Techniques; D007668:Kidney; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
D020690:GTPase-Activating Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016184:Receptors, Colony-Stimulating Factor; D011993:Recombinant Fusion Proteins; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D010738:Type C Phospholipases