Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1997 Dec;17(12):7398–7406. doi: 10.1128/mcb.17.12.7398

Complementation of growth factor receptor-dependent mitogenic signaling by a truncated type I phosphatidylinositol 4-phosphate 5-kinase.

J N Davis 1, C O Rock 1, M Cheng 1, J B Watson 1, R A Ashmun 1, H Kirk 1, R J Kay 1, M F Roussel 1
PMCID: PMC232595  PMID: 9372970

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.

Full Text

The Full Text of this article is available as a PDF (829.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Afar D. E., McLaughlin J., Sherr C. J., Witte O. N., Roussel M. F. Signaling by ABL oncogenes through cyclin D1. Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9540–9544. doi: 10.1073/pnas.92.21.9540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ashmun R. A., Look A. T., Roberts W. M., Roussel M. F., Seremetis S., Ohtsuka M., Sherr C. J. Monoclonal antibodies to the human CSF-1 receptor (c-fms proto-oncogene product) detect epitopes on normal mononuclear phagocytes and on human myeloid leukemic blast cells. Blood. 1989 Feb 15;73(3):827–837. [PubMed] [Google Scholar]
  3. Baass P. C., Di Guglielmo G. M., Authier F., Posner B. I., Bergeron J. J. Compartmentalized signal transduction by receptor tyrosine kinases. Trends Cell Biol. 1995 Dec;5(12):465–470. doi: 10.1016/s0962-8924(00)89116-3. [DOI] [PubMed] [Google Scholar]
  4. Bazenet C. E., Ruano A. R., Brockman J. L., Anderson R. A. The human erythrocyte contains two forms of phosphatidylinositol-4-phosphate 5-kinase which are differentially active toward membranes. J Biol Chem. 1990 Oct 15;265(29):18012–18022. [PubMed] [Google Scholar]
  5. Burgoyne R. D. Phosphoinositides in vesicular traffic. Trends Biochem Sci. 1994 Feb;19(2):55–57. doi: 10.1016/0968-0004(94)90032-9. [DOI] [PubMed] [Google Scholar]
  6. Carlberg K., Tapley P., Haystead C., Rohrschneider L. The role of kinase activity and the kinase insert region in ligand-induced internalization and degradation of the c-fms protein. EMBO J. 1991 Apr;10(4):877–883. doi: 10.1002/j.1460-2075.1991.tb08020.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carpenter C. L., Cantley L. C. Phosphoinositide kinases. Biochemistry. 1990 Dec 25;29(51):11147–11156. doi: 10.1021/bi00503a001. [DOI] [PubMed] [Google Scholar]
  8. Chen C., Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. doi: 10.1128/mcb.7.8.2745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. De Camilli P., Emr S. D., McPherson P. S., Novick P. Phosphoinositides as regulators in membrane traffic. Science. 1996 Mar 15;271(5255):1533–1539. doi: 10.1126/science.271.5255.1533. [DOI] [PubMed] [Google Scholar]
  10. Fukami K., Sawada N., Endo T., Takenawa T. Identification of a phosphatidylinositol 4,5-bisphosphate-binding site in chicken skeletal muscle alpha-actinin. J Biol Chem. 1996 Feb 2;271(5):2646–2650. doi: 10.1074/jbc.271.5.2646. [DOI] [PubMed] [Google Scholar]
  11. Hanks S. K., Hunter T. Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 1995 May;9(8):576–596. [PubMed] [Google Scholar]
  12. Hay J. C., Fisette P. L., Jenkins G. H., Fukami K., Takenawa T., Anderson R. A., Martin T. F. ATP-dependent inositide phosphorylation required for Ca(2+)-activated secretion. Nature. 1995 Mar 9;374(6518):173–177. doi: 10.1038/374173a0. [DOI] [PubMed] [Google Scholar]
  13. Hyvönen M., Macias M. J., Nilges M., Oschkinat H., Saraste M., Wilmanns M. Structure of the binding site for inositol phosphates in a PH domain. EMBO J. 1995 Oct 2;14(19):4676–4685. doi: 10.1002/j.1460-2075.1995.tb00149.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ishihara H., Shibasaki Y., Kizuki N., Katagiri H., Yazaki Y., Asano T., Oka Y. Cloning of cDNAs encoding two isoforms of 68-kDa type I phosphatidylinositol-4-phosphate 5-kinase. J Biol Chem. 1996 Sep 27;271(39):23611–23614. doi: 10.1074/jbc.271.39.23611. [DOI] [PubMed] [Google Scholar]
  15. Johnson L. N., Noble M. E., Owen D. J. Active and inactive protein kinases: structural basis for regulation. Cell. 1996 Apr 19;85(2):149–158. doi: 10.1016/s0092-8674(00)81092-2. [DOI] [PubMed] [Google Scholar]
  16. Joly M., Kazlauskas A., Corvera S. Phosphatidylinositol 3-kinase activity is required at a postendocytic step in platelet-derived growth factor receptor trafficking. J Biol Chem. 1995 Jun 2;270(22):13225–13230. doi: 10.1074/jbc.270.22.13225. [DOI] [PubMed] [Google Scholar]
  17. Joly M., Kazlauskas A., Fay F. S., Corvera S. Disruption of PDGF receptor trafficking by mutation of its PI-3 kinase binding sites. Science. 1994 Feb 4;263(5147):684–687. doi: 10.1126/science.8303278. [DOI] [PubMed] [Google Scholar]
  18. Langer S. J., Bortner D. M., Roussel M. F., Sherr C. J., Ostrowski M. C. Mitogenic signaling by colony-stimulating factor 1 and ras is suppressed by the ets-2 DNA-binding domain and restored by myc overexpression. Mol Cell Biol. 1992 Dec;12(12):5355–5362. doi: 10.1128/mcb.12.12.5355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ling L. E., Schulz J. T., Cantley L. C. Characterization and purification of membrane-associated phosphatidylinositol-4-phosphate kinase from human red blood cells. J Biol Chem. 1989 Mar 25;264(9):5080–5088. [PubMed] [Google Scholar]
  20. Loijens J. C., Boronenkov I. V., Parker G. J., Anderson R. A. The phosphatidylinositol 4-phosphate 5-kinase family. Adv Enzyme Regul. 1996;36:115–140. doi: 10.1016/0065-2571(95)00005-4. [DOI] [PubMed] [Google Scholar]
  21. Lopata M. A., Cleveland D. W., Sollner-Webb B. High level transient expression of a chloramphenicol acetyl transferase gene by DEAE-dextran mediated DNA transfection coupled with a dimethyl sulfoxide or glycerol shock treatment. Nucleic Acids Res. 1984 Jul 25;12(14):5707–5717. doi: 10.1093/nar/12.14.5707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. M A L., M F., J S., K F. Regulatory recruitment of signalling molecules to the cell membrane by pleckstrinhomology domains. Trends Cell Biol. 1997 Jun;7(6):237–242. doi: 10.1016/S0962-8924(97)01065-9. [DOI] [PubMed] [Google Scholar]
  23. Morgenstern J. P., Land H. A series of mammalian expression vectors and characterisation of their expression of a reporter gene in stably and transiently transfected cells. Nucleic Acids Res. 1990 Feb 25;18(4):1068–1068. doi: 10.1093/nar/18.4.1068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rettenmier C. W., Chen J. H., Roussel M. F., Sherr C. J. The product of the c-fms proto-oncogene: a glycoprotein with associated tyrosine kinase activity. Science. 1985 Apr 19;228(4697):320–322. doi: 10.1126/science.2580348. [DOI] [PubMed] [Google Scholar]
  25. Rettenmier C. W., Roussel M. F. Differential processing of colony-stimulating factor 1 precursors encoded by two human cDNAs. Mol Cell Biol. 1988 Nov;8(11):5026–5034. doi: 10.1128/mcb.8.11.5026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Roussel M. F., Ashmun R. A., Sherr C. J., Eisenman R. N., Ayer D. E. Inhibition of cell proliferation by the Mad1 transcriptional repressor. Mol Cell Biol. 1996 Jun;16(6):2796–2801. doi: 10.1128/mcb.16.6.2796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Roussel M. F., Cleveland J. L., Shurtleff S. A., Sherr C. J. Myc rescue of a mutant CSF-1 receptor impaired in mitogenic signalling. Nature. 1991 Sep 26;353(6342):361–363. doi: 10.1038/353361a0. [DOI] [PubMed] [Google Scholar]
  28. Roussel M. F., Davis J. N., Cleveland J. L., Ghysdael J., Hiebert S. W. Dual control of myc expression through a single DNA binding site targeted by ets family proteins and E2F-1. Oncogene. 1994 Feb;9(2):405–415. [PubMed] [Google Scholar]
  29. Roussel M. F., Rettenmier C. W., Look A. T., Sherr C. J. Cell surface expression of v-fms-coded glycoproteins is required for transformation. Mol Cell Biol. 1984 Oct;4(10):1999–2009. doi: 10.1128/mcb.4.10.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Roussel M. F., Sherr C. J., Barker P. E., Ruddle F. H. Molecular cloning of the c-fms locus and its assignment to human chromosome 5. J Virol. 1983 Dec;48(3):770–773. doi: 10.1128/jvi.48.3.770-773.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Roussel M. F., Shurtleff S. A., Downing J. R., Sherr C. J. A point mutation at tyrosine-809 in the human colony-stimulating factor 1 receptor impairs mitogenesis without abrogating tyrosine kinase activity, association with phosphatidylinositol 3-kinase, or induction of c-fos and junB genes. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6738–6742. doi: 10.1073/pnas.87.17.6738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Roussel M. F. Signal transduction by the macrophage-colony-stimulating factor receptor (CSF-1R). J Cell Sci Suppl. 1994;18:105–108. doi: 10.1242/jcs.1994.supplement_18.15. [DOI] [PubMed] [Google Scholar]
  33. Roussel M. F., Theodoras A. M., Pagano M., Sherr C. J. Rescue of defective mitogenic signaling by D-type cyclins. Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6837–6841. doi: 10.1073/pnas.92.15.6837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Schlessinger J. SH2/SH3 signaling proteins. Curr Opin Genet Dev. 1994 Feb;4(1):25–30. doi: 10.1016/0959-437x(94)90087-6. [DOI] [PubMed] [Google Scholar]
  35. Schlessinger J., Ullrich A. Growth factor signaling by receptor tyrosine kinases. Neuron. 1992 Sep;9(3):383–391. doi: 10.1016/0896-6273(92)90177-f. [DOI] [PubMed] [Google Scholar]
  36. Sherr C. J. Mitogenic response to colony-stimulating factor 1. Trends Genet. 1991 Nov-Dec;7(11-12):398–402. doi: 10.1016/0168-9525(91)90263-p. [DOI] [PubMed] [Google Scholar]
  37. Vallance S. J., Lee H. M., Roussel M. F., Shurtleff S. A., Kato J. Y., Strom D. K., Sherr C. J. Monoclonal antibodies to mammalian D-type G1 cyclins. Hybridoma. 1994 Feb;13(1):37–44. doi: 10.1089/hyb.1994.13.37. [DOI] [PubMed] [Google Scholar]
  38. Vieira A. V., Lamaze C., Schmid S. L. Control of EGF receptor signaling by clathrin-mediated endocytosis. Science. 1996 Dec 20;274(5295):2086–2089. doi: 10.1126/science.274.5295.2086. [DOI] [PubMed] [Google Scholar]
  39. Wang Z., Moran M. F. Requirement for the adapter protein GRB2 in EGF receptor endocytosis. Science. 1996 Jun 28;272(5270):1935–1939. doi: 10.1126/science.272.5270.1935. [DOI] [PubMed] [Google Scholar]
  40. Whitehead I., Kirk H., Kay R. Expression cloning of oncogenes by retroviral transfer of cDNA libraries. Mol Cell Biol. 1995 Feb;15(2):704–710. doi: 10.1128/mcb.15.2.704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Wong K., Meyers ddR, Cantley L. C. Subcellular locations of phosphatidylinositol 4-kinase isoforms. J Biol Chem. 1997 May 16;272(20):13236–13241. doi: 10.1074/jbc.272.20.13236. [DOI] [PubMed] [Google Scholar]
  42. Xu W., Harrison S. C., Eck M. J. Three-dimensional structure of the tyrosine kinase c-Src. Nature. 1997 Feb 13;385(6617):595–602. doi: 10.1038/385595a0. [DOI] [PubMed] [Google Scholar]
  43. Yamamoto A., DeWald D. B., Boronenkov I. V., Anderson R. A., Emr S. D., Koshland D. Novel PI(4)P 5-kinase homologue, Fab1p, essential for normal vacuole function and morphology in yeast. Mol Biol Cell. 1995 May;6(5):525–539. doi: 10.1091/mbc.6.5.525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Zhou M. M., Ravichandran K. S., Olejniczak E. F., Petros A. M., Meadows R. P., Sattler M., Harlan J. E., Wade W. S., Burakoff S. J., Fesik S. W. Structure and ligand recognition of the phosphotyrosine binding domain of Shc. Nature. 1995 Dec 7;378(6557):584–592. doi: 10.1038/378584a0. [DOI] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES