| Regulation of cell proliferation
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| Cells of a multicellular organism have to receive specific positive signals in order to grow and divide. Many of these signals are in the form of polypeptide hormones (e.g. insulin), growth factors (e.g. platelet-derived growth factor, PDGF) or cytokines (e.g. interleukins, designated IL-1 to IL-29). These growth factors bind to specific cell-surface receptors and initiate intracellular signaling cascades that ultimately act to counter those negative controls in resting cells that prevent growth and block cell cycle progression. Proliferation of most cell types generally requires signaling via a specific combination of growth factors, rather than stimulation by a single growth factor; thus a relatively small number of growth factors can selectively regulate the proliferation of many cell types. Moreover, although most factors that stimulate cell growth also stimulate cell proliferation, some factors will induce cell growth but not division. This reflects the reality that, within an organism, individual cell types vary enormously in size. Indeed, some cells, such as neurons (in the G0-phase), grow very large without ever dividing. Furthermore, although proliferating cells stop growing when they are deprived of growth factors, they continue to progress through the cell cycle until they reach the point in the G1-phase at which they can enter the G0-phase or resting state.
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Growth factors bind to specific cell-surface receptors, which are generally transmembrane proteins with cytoplasmic protein tyrosine kinase domains (see also chapter 38). There are now about 50 known growth factors; PDGF was one of the first to be identified. The growth and proliferative responses to PDGF have proved to be prototypic of many other growth factors and include:
- immediate increase in intracellular Ca2+, indicative of initiation of transmembrane signaling (see Chapter 38);
- reorganization of actin stress fibers, which is necessary for the anchorage-dependence of cell attachment that is required for cell cycle progression;
- activation, nuclear translocation, or both, of transcription factors (see Chapter 33) that bind to regulatory regions of the DNA of genes that are responsive to the particular growth factor. These transcription factors regulate the transcription of early response genes, which often encode additional transcription factors that are necessary for the induction of components of the cell cycle machinery such as cyclin proteins and, ultimately:
- DNA synthesis and cell division.
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| Growth factors activate distinct combinations of signal transducers (see Chapter 38) and transcription factors to dictate the precise repertoire of genes that is induced, thereby enabling the initiation of characteristic differential classes of responses.
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| Figure 41.2 Recruitment of the downstream signaling element scaffold to the activated PDGF receptor. Growth factor ligation of the receptor induces dimerization and activation of the tyrosine kinase intrinsic to the receptor cytoplasmic domains, leading to tyrosine phosphorylation (transphosphorylation, P) of the dimerized receptor at specific sites on the cytoplasmic domains (A). Docking sites thus created (B) enable protein-protein interactions that lead to recruitment and activation of downstream signaling enzymes, for example phospholipase C (PLC), GTPase-activating protein (GAP), protein tyrosine kinases (PTKs) such as Src, phosphotyrosine phosphatases such as SHP (SH2 domain-containing phosphatase), and adapter molecules such as Grb2 (which recruits Ras). |
| THE ROLE OF PROTEIN TYROSINE KINASES IN SIGNAL TRANSDUCTION |
| Protein tyrosine kinase (PTK)-dependent interactions in cell signaling |
PTKs are enzymes that transfer the γ-phosphate group of ATP to tyrosine residues on target substrate proteins. The term 'protein tyrosine kinase' is a generic term for a large superfamily of enzymes comprising both transmembrane-spanning receptors with an intrinsic tyrosine kinase activity in their cytoplasmic domains and a wide range of subfamilies of cytoplasmic tyrosine kinases such as the Src, Abl or Janus kinase (JAK) families. Tyrosine phosphorylation, which is a covalent modification of proteins, provides a rapid and reversible (by the action of protein tyrosine phosphatases) mechanism of modifying the enzymic activity of target proteins. In addition, it can modify their ability to act as adapter molecules to recruit other signaling molecules to the protein networks involved in transmembrane cell signaling. For example, the tyrosine phosphorylation of receptors or signaling molecules creates 'docking sites' that allow protein-protein interactions leading to recruitment of downstream signal transducers. Signal transducers are recruited to these phosphorylated tyrosines by virtue of protein-protein interaction domains, called SH2 domains, contained within the sequence of many signal transducers. SH2 stands for Src-homology region 2, from the cytoplasmic Src tyrosine kinase, a signal transducing element in which this protein domain was first characterized. SH2 domains comprise approximately 100 amino acids and specifically recognize a phosphotyrosine plus the three amino acids immediately C-terminal to that phosphotyrosine. |
| Growth factor binding generally induces receptor dimerization and activation of the tyrosine kinase intrinsic to the receptor, causing phosphorylation of the dimerized receptor at specific sites on its cytoplasmic domains (transphosphorylation; Fig. 41.2). This tyrosine phosphorylation of the receptor creates 'docking sites' that allow protein-protein interactions, leading to recruitment and activation of signaling enzymes or 'adapter molecules', which are signal transducers that serve as enzyme modulators for signaling enzymes. Transphosphorylation of receptor cytoplasmic domains thus allows recruitment and activation of a scaffold
of signal transduction elements (see Fig. 41.2) such as phospholipase C-γ (PLC-γ), GTPase-activating protein (GAP), protein tyrosine kinases (PTKs) such as Src, Fyn and Abl, phosphotyrosine phosphatases (PTPases) and adapter molecules such as Shc or Grb2, which we will discuss in more detail below.
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