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The ability of cells to receive and respond to extracellular signals is a critical process in the embryonic development of multicellular organisms as well as for the maintenance and survival of mature tissues in the adult. Changes in the physical or chemical environment of the cell can result in modifications of cell metabolism, morphology, movement, or proliferation. These responses are brought about by elaborate networks of intracellular signals transmitted by changes in protein phosphorylation and enzymatic activity, localization and the formation of protein–protein complexes. Cellular responses are triggered by the recognition of extracellular signals at the cell surface, resulting in the activation of linked cytoplasmic and nuclear biochemical cascades. These signal transduction pathways control cellular processes that range from the generalized control of cell proliferation and survival to specialized functions such as the immune response and angiogenesis. When dysregulated, signaling pathways involved in normal growth, adhesion and development contribute to malignant transformation in human cells. This knowledge has led to the development of new cancer therapeutics that specifically target aberrant signal transduction pathways. This chapter explores how signal transduction pathways are organized and highlights ongoing drug discovery efforts to target these pathways.
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8.2 GROWTH FACTOR SIGNALING PATHWAYS
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8.2.1 Extracellular Growth Factors and Receptor Tyrosine Kinases
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In multicellular organisms, cell regulation is controlled by secreted polypeptide molecules called growth factors or cytokines, by antigen stimulation of immune cells, or by cell contact with neighboring cells and surrounding extracellular matrix. Our most detailed understanding of signal transduction pathways comes from studies of soluble growth factors and their interaction with complementary growth factor receptors expressed on responsive cells. The interaction between growth factors and receptors on the cell surface leads to the modification of intracellular biochemical signaling pathways that control cellular responses, especially cell proliferation. Cellular regulation also occurs through direct cell to cell contact or cell contact with its surrounding extracellular matrix (as discussed in Chap. 10, Sec. 10.2).
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Growth factors were first identified in cell culture medium as necessary to sustain mammalian cell survival and proliferation. One of the characteristics of malignant transformation was found to be relative independence from the action of external growth factors. Many polypeptide growth factors have been identified with diverse functions in normal embryonic development and tissue homeostasis but only a few factors are associated with the process of malignant transformation.
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Polypeptide growth factors influence cell processes, such as growth, proliferation, differentiation, survival, and metabolism, via their interaction with specific transmembrane receptor protein tyrosine kinases (RPTKs). Most are small monomeric (ie, single-chain) polypeptides, such as the epidermal growth factor (EGF) and members of the fibroblast growth factor (FGF) family. There are also dimeric polypeptide growth factors (ie, those containing 2 chains of amino acids), such as platelet-derived growth factor (PDGF). In addition to being freely diffusible, growth factors can also reside in spatially restricted domains within an organism, ...