COMPLEMENTATION OF GROWTH-FACTOR RECEPTOR-DEPENDENT MITOGENIC SIGNALING BY A TRUNCATED TYPE-I PHOSPHATIDYLINOSITOL 4-PHOSPHATE 5-KINASE

Citation
Jn. Davis et al., COMPLEMENTATION OF GROWTH-FACTOR RECEPTOR-DEPENDENT MITOGENIC SIGNALING BY A TRUNCATED TYPE-I PHOSPHATIDYLINOSITOL 4-PHOSPHATE 5-KINASE, Molecular and cellular biology, 17(12), 1997, pp. 7398-7406
Citations number
47
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biology,"Cell Biology
ISSN journal
0270-7306
Volume
17
Issue
12
Year of publication
1997
Pages
7398 - 7406
Database
ISI
SICI code
0270-7306(1997)17:12<7398:COGRMS>2.0.ZU;2-6
Abstract
Substitution of phenylalanine for tyrosine at codon 809 (Y809F) of the human colony-stimulating factor 1 (CSF-1) receptor (CSF-1R) impairs l igand-stimulated tyrosine kinase activity, prevents induction of c-MYC and cyclin D1 genes, and blocks CSF-1-dependent progression through t he G(1) phase of the cell cycle, We devised an unbiased genetic screen to isolate genes that restore the ability of CSF-1 to stimulate growt h in cells that express mutant CSF-1R (Y809F). This screen led us to i dentify a truncated form of the murine type I beta phosphatidylinosito l 4-phosphate 5-kinase (mPIP5K-I beta). This truncated protein lacks r esidues 1 to 238 of mPIP5K-I beta and is catalytically inactive. When we transfected cells expressing CSF-1R (Y809F) with mPIP5K-I beta (Del ta 1-238), CSF-1-dependent induction of c-MYC and cyclin D1 was restor ed and ligand-dependent cell proliferation was sustained. CSF-1 normal ly triggers the rapid disappearance of CSF-1R (Y809F) from the cell su rface; however, transfection of cells with mPIP5K-I beta (Delta 1-238) stabilized CSF-1R (Y809F) expression on the cell surface, resulting i n elevated levels of ligand-activated CSF-1R (Y809F). These results su ggest a role for PIP5K-I beta in receptor endocytosis and that the tru ncated enzyme compensated for a mitogenically defective CSF-1R by inte rfering with this process.