STAT Protein Recruitment and Activation in c-Kit Deletion Mutants

• Published in: The Journal of biological chemistry 1999-06, Vol.274 (24), p.16965-16972
• Main Authors: Brizzi, M F, Dentelli, P, Rosso, A, Yarden, Y, Pegoraro, L
• Format: Article
• Language: English
• Subjects: Binding Sites; Biological Transport; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Cell Compartmentation; Cell Nucleus - metabolism; Dimerization; DNA-Binding Proteins - metabolism; Interferon-Stimulated Gene Factor 3; Milk Proteins; Mutation; Phosphorylation; Protein Binding; Proto-Oncogene Proteins c-kit - genetics; Response Elements; Sequence Deletion; Signal Transduction; STAT5 Transcription Factor; Stem Cell Factor - pharmacology; Trans-Activators - metabolism; Transcription Factors - metabolism; Tyrosine - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.24.16965

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: STAT1α, 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 STAT1α, possibly in the form of homodimers, binds to the sis -inducible DNA element, STAT5 proteins, either as STAT5A/STAT5B or STAT5/STAT1α heterodimers, bind to the prolactin-inducible element of the β-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 STAT1α 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.