The Role of Phosphorylation in Growth Control and Malignant Transformation
Experiments with cultured cells suggest that the growth of mammalian cells is regulated largely by growth factors and inhibitors acting at the G0/G1 border in cell cycle. Growth factors are mostly polypeptide in nature (e.g. EGF, PDGF, FGF, IGF-1, bombesin) and range in mass from 2,000 to 70,000 daltons. Cells responsive to a given growth factor have specific cell surface receptors, usually numbering between 103 and 106 per cell, with a high affinity (Kd 10-8 to 10-11) and specificity for their ligand. Occupancy of these receptors results in the transduction of a signal across the membrane to the cytoplasm, the nature of which will be discussed below. Bona fide growth inhibitors have only recently been purified to homogeneity (e.g. TGF-β, interferon), although their existence had been surmised for many years. Their mode of action is not understood, but, like the polypeptide growth factors, growth inhibitors have specific high affinity surface receptors, which presumably transduce signals to the cytoplasm. Another external component essential for cell growth is the extracellular matrix, comprised of proteins like fibronectin, laminin, and collagen, and the glycosaminoglycans. Adherent cells will not grow in the absence of an extracellular matrix, but most cells are capable of elaborating their own matrix. There are specific surface receptors for these matrix proteins, but it is not yet known whether the binding of ligand to this type of receptor causes a signal transduction event.
KeywordsGrowth Factor Receptor Tyrosine Phosphorylation Protein Kinase Activity Mitogenic Response Protein Kinase Domain
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- 3.A. Ullrich, L. Coussens, J. S. Hayflick, T. J. Dull, A. Gray, A. W. Tam, J. Lee, Y. Yarden, T. A. Libermann, J. Schlessinger, J. Downward, E. L. V. Mayes, N. Whittle, M. D. Waterfield, and P. H. Seeburg, Human EGF receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309:418 (1984).PubMedCrossRefGoogle Scholar
- 5.A. Ullrich, J. R. Bell, E. Y. Chen, R. Herrera, L. M. Petruzelli, T. J. Dull, A. Gray, L. Coussens, M. Isubokawa, A. Mason, P. H. Seeburg, C. Grunfeld, O. M. Rosen, and J. Ramachandran, Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313, 756 (1985).PubMedCrossRefGoogle Scholar
- 6.Y. Yarden, J. A. Escobedo, W. J. Kuang, T. L. Yang-Feng, T. O. Daniel, P. M. Tremble, E. Y. Chen, M. E. Ando, R. N. Harkins, U. Francke, V. A. Fried, A. Ullrich, and L. T. Williams, Structure of the receptor for PDGF helps define a family of closely-related growth factor receptors. Nature 323:226 (1986).PubMedCrossRefGoogle Scholar
- 7.A. Ullrich, A. Gray, A. W. Tam, T. L. Yang-Feng, M. Tsubokawa, C. Collins, W. Renzel, T. LeBon, S. Kathuria, E. Chen, S. Jacobs, U. Francke, J. Ramachandran, and Y. Fujita-Yamaguchi, Insulin-like growth factor 1 primary structure: comparison with insulin receptor suggests structural determinants that define functional sepcificity, EMBO J. 5:2503 (1986).PubMedGoogle Scholar
- 10.D. A. Cirillo, G. Gaudino, L. Naldini, and P. M. Comoglio, Receptor for bombesin with associated tyrosine kinase activity, Mol. Cell. Biol. 6:4641 (1986).Google Scholar
- 15.T. Hunter, Oncogenes and proto-oncogenes: how do they differ? J. Natl. Cane. Inst. 73:773 (1984).Google Scholar
- 18.P. M. Coussens, J. A. Cooper, T. Hunter, and D. Shalloway, Restriction in vitro and in vivo tyrosine protein kinase activities of relative to Cell. Biol. 5:2753 (1985).Google Scholar
- 22.R. M. Kris, I. Lax, W. Gullick, M. D. Waterfield, A. Ullrich, M. Fridkin, and J. Schlessinger, Antibodies against synthetic peptides as a probe for the kinase activity of the avian EGF receptor and v-erb-B protein, Cell 40:609 (1986).Google Scholar
- 23.T. Gilmore, J. E. DeClue, and G. S. Martin, Protein phosphorylation at tyrosine induced by the v-erb-B protein, Cell 40:619 (1986).Google Scholar
- 27.K. S. Huang, B. P. Wallner, R. J. Mattaliano, R. Tizard, C. Burne, A. Frey, C. Hession, P. McGray, L. K. Sinclair, E. P. Chow, J. L. Browning, K. L. Ramachandran, J. Tang, J. E. Smart, and R. B. Pepinsky, Two human 35 kd inhibitors of phospholipase A2 are related to substrates of and of the EGF receptor kinase, Cell 46:191 (1986).PubMedCrossRefGoogle Scholar
- 34.J. R. Woodgett, T. Hunter, and K. L. Gould, Protein kinase C and its role in cell growth, in: “Cell Membranes: Methods and Reviews,” E. L. Elson, W. A. Frazier, and L. Glaser, eds.. Plenum Publishing Co. New York (1987).Google Scholar