title: Complementation of growth factor receptor-dependent mitogenic signaling by a truncated type I phosphatidylinositol 4-phosphate 5-kinase.
abstract: Substitution of phenylalanine for tyrosine at codon 809 (Y809F) of the human colony-stimulating factor 1 (CSF-1) receptor (CSF-1R) impairs ligand-stimulated tyrosine kinase activity, prevents induction of c-MYC and cyclin D1 genes, and blocks CSF-1-dependent progression through the G1 phase of the cell cycle. We devised an unbiased genetic screen to isolate genes that restore the ability of CSF-1 to stimulate growth in cells that express mutant CSF-1R (Y809F). This screen led us to identify a truncated form of the murine type Ibeta phosphatidylinositol 4-phosphate 5-kinase (mPIP5K-Ibeta). This truncated protein lacks residues 1 to 238 of mPIP5K-Ibeta and is catalytically inactive. When we transfected cells expressing CSF-1R (Y809F) with mPIP5K-Ibeta (delta1-238), CSF-1-dependent induction of c-MYC and cyclin D1 was restored and ligand-dependent cell proliferation was sustained. CSF-1 normally triggers the rapid disappearance of CSF-1R (Y809F) from the cell surface; however, transfection of cells with mPIP5K-Ibeta (delta1-238) stabilized CSF-1R (Y809F) expression on the cell surface, resulting in elevated levels of ligand-activated CSF-1R (Y809F). These results suggest a role for PIP5K-Ibeta in receptor endocytosis and that the truncated enzyme compensated for a mitogenically defective CSF-1R by interfering with this process.
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: J N
authors.initials: JN
authors.lastname: Davis
authors.forename: C O
authors.initials: CO
authors.lastname: Rock
authors.forename: M
authors.initials: M
authors.lastname: Cheng
authors.forename: J B
authors.initials: JB
authors.lastname: Watson
authors.forename: R A
authors.initials: RA
authors.lastname: Ashmun
authors.forename: H
authors.initials: H
authors.lastname: Kirk
authors.forename: R J
authors.initials: RJ
authors.lastname: Kay
authors.forename: M F
authors.initials: MF
authors.lastname: Roussel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D002460:Cell Line; D003115:Colony-Stimulating Factors / Q000494:pharmacology; D019938:Cyclin D1 / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004705:Endocytosis; D016259:Genes, myc; D005816:Genetic Complementation Test; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D003115:Colony-Stimulating Factors; D017931:DNA Primers; D018076:DNA, Complementary; D016184:Receptors, Colony-Stimulating Factor; D019938:Cyclin D1; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase