STAT protein recruitment and activation in c-Kit deletion mutants.
Stem cell factor (SCF) and its tyrosine kinase receptor, c-Kit, play a crucial role in regulating migration and proliferation of melanoblasts, germ cells, and hemopoietic cell progenitors by activating a number of intracellular signaling molecules. Here we report that SCF stimulation of myeloid cells or fibroblasts ectopically expressing c-Kit induces physical association with and tyrosine phosphorylation of three signal transducers and activators of transcription (STATs) as follows: STAT1alpha, STAT5A, and STAT5B. Other STAT proteins are not recruited upon SCF stimulation. Recruitment of STATs leads to their dimerization, nuclear translocation, and binding to specific promoter-responsive elements. Whereas STAT1alpha, possibly in the form of homodimers, binds to the sis-inducible DNA element, STAT5 proteins, either as STAT5A/STAT5B or STAT5/STAT1alpha heterodimers, bind to the prolactin-inducible element of the beta-casein promoter. The tyrosine kinase activity of Kit appears essential for STAT activation since a kinase-defective mutant lacking a kinase insert domain was inactive in STAT signaling. However, another mutant that lacked the carboxyl-terminal region retained STAT1alpha activation and nuclear translocation but was unable to fully activate STAT5 proteins, although it mediated their transient phosphorylation. These results indicate that different intracellular domains of c-Kit are involved in activation of the various STAT proteins.
Brizzi
M F
MF
Department of Internal Medicine, University of Turin, Turin 10126, Italy.
Dentelli
P
P
Rosso
A
A
Yarden
Y
Y
Pegoraro
L
L
D001665:Binding Sites; D001692:Biological Transport; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002451:Cell Compartmentation; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D050832:Interferon-Stimulated Gene Factor 3; D008894:Milk Proteins; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020218:Response Elements; D050799:STAT5 Transcription Factor; D017384:Sequence Deletion; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D004268:DNA-Binding Proteins; D050832:Interferon-Stimulated Gene Factor 3; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; D019089:Stem Cell Factor; D015534:Trans-Activators; D014157:Transcription Factors; C079868:gamma interferon activation factor; D014443:Tyrosine; D019009:Proto-Oncogene Proteins c-kit