Interaction and functional cooperation between the serine/threonine kinase bone morphogenetic protein type II receptor with the tyrosine kinase stem cell factor receptor.
Transmembrane receptors with intrinsic serine/threonine or tyrosine kinase domains regulate vital functions of cells in multicellular eukaryotes, e.g., differentiation, apoptosis, and proliferation. Here, we show that bone morphogenetic protein type II receptor (BMPR-II) which has a serine/threonine kinase domain, and stem cell factor receptor (c-kit) which contains a tyrosine kinase domain form a complex in vitro and in vivo; the interaction is induced upon treatment of cells with BMP2 and SCF. Stem cell factor (SCF) modulated BMP2-dependent activation of Smad1/5/8 and phosphorylation of Erk kinase. SCF also enhanced BMP2-dependent differentiation of C2C12 cells. We found that BMPR-II was phosphorylated at Ser757 upon co-expression with and activation of c-kit. BMPR-II phosphorylation required intact kinase activity of BMPR-II. Abrogation of the c-kit/SCF-dependent phosphorylation of BMPR-II at the Ser757 interfered with the cooperative effect of BMP2 and SCF. Our data suggest that the complex formation between c-kit and BMPR-II leads to phosphorylation of BMPR-II at Ser757, which modulates BMPR-II-dependent signaling.
Hassel
Sylke
S
Ludwig Institute for Cancer Research, Biomedical Centre, Uppsala, Sweden.
Yakymovych
Mariya
M
Hellman
Ulf
U
Rönnstrand
Lars
L
Knaus
Petra
P
Souchelnytskyi
Serhiy
S
D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D019556:COS Cells; D002454:Cell Differentiation; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D014162:Transfection
D051785:Smad Proteins; D019009:Proto-Oncogene Proteins c-kit; D048049:Extracellular Signal-Regulated MAP Kinases; D052006:Bone Morphogenetic Protein Receptors, Type II