STAT protein recruitment and activation in c-Kit deletion mutants

Citation
Mf. Brizzi et al., STAT protein recruitment and activation in c-Kit deletion mutants, J BIOL CHEM, 274(24), 1999, pp. 16965-16972
Citations number
48
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
274
Issue
24
Year of publication
1999
Pages
16965 - 16972
Database
ISI
SICI code
0021-9258(19990611)274:24<16965:SPRAAI>2.0.ZU;2-H
Abstract
Stem cell factor (SCF) and its tyrosine kinase receptor, c-Kit, play a cruc ial role in regulating migration and proliferation of melanoblasts, germ ce lls, and hemopoietic cell progenitors by activating a number of intracellul ar signaling molecules. Here we report that SCF stimulation of myeloid cell s or fibroblasts ectopically expressing c-Kit induces physical association with and tyrosine phosphorylation of three signal transducers and activator s of transcription (STATs) as follows: STAT1 alpha, STAT5A, and STAT5B. Oth er STAT proteins are not recruited upon SCF stimulation. Recruitment of STA Ts leads to their dimerization, nuclear translocation, and binding to speci fic promoter-responsive elements. Whereas STAT1 alpha, possibly in the form of homodimers, binds to the sis-inducible DNA element, STAT5 proteins, eit her as STAT5A/STAT5B or STAT5/STAT1 alpha heterodimers, bind to the prolact in-inducible element of the beta-casein promoter. The tyrosine kinase activ ity of Kit appears essential for STAT activation since a kinase-defective m utant lacking a kinase insert domain was inactive in STAT signaling. Howeve r, another mutant that lacked the carboxyl-terminal region retained STAT1 a lpha activation and nuclear translocation but was unable to fully activate STATE proteins, although it mediated their transient phosphorylation, These results indicate that different intracellular domains of c-Kit are involve d in activation of the various STAT proteins.