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
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.