Human Biochemistry, Volume 2 - Murray R. 1993

Special Topics
Cancer, Oncogenes, and Growth Factors
Polypeptide Growth Factors — Biochemical Mechanisms of Growth Factor Action

Relatively little is known about the MOLECULAR MECHANISMS OF growth factor action. Like polypeptide Hormones (see Chapter 44), growth factors must transmit a signal across Cell/30.html">The Plasma Membrane and into The Cell (transmembrane signaling). Ultimately, the growth factor signal influences one or more mitosis-related processes. Most growth factors bind to highly specific receptors located on the plasma membrane of target Cells. The genes for the epidermal growth factor (EGF) and Insulin receptors have been cloned, and their receptor structures

have been elucidated. They consist of a short transmembrane segment, as well as extracellular and cytoplasmic domains that vary in length among different receptors. Ligands bind to the extracellular domains. Several receptors (such as those for epidermal growth factor, insulin, and platelet-derived growth factor) exhibit Tyrosine protein kinase activity (recall that the product of the v-src Gene possesses the same activity). This kinase activity is localized to the cytoplasmic domains of the receptors, where its function is to autophosphorylate the receptor protein. The receptor-Ligand complex undergoes endocytosis via coated vesicles (see LDL receptors, Chapter 27); it remains unclear whether these receptors recycle back to the cell surface. The mechanisms of transmembrane signaling by growth factors are still under active investigation, and it has been shown that they vary among different factors. As an example, let us consider The sequence of events triggered by platelet-derived growth factor. This factor stimulates The activity of phospholipase C, which hydrolyzes phosphatidylinositol 4,5-bisphosphate into Inositol trisphosphate and diacylglycerol (see above, v-src, as well as Fig. 44.5). Inositol trisphosphate triggers the release of intracellular Ca²⁺, whereas diacylglycerol activates protein kinase C, thereby initiating numerous intracellular processes. Subsequent Hydrolysis of diacylglycerol by phospholipase A₂ releases arachidonic acid (among other Fatty acids), which is involved in the synthesis of highly biologically active Prostaglandins and Leukotrienes (see Chapter 24). Incubation of cells with a platelet-derived growth factor preparation can lead to rapid (ranging from a few minutes to 1–2 hours) activation of cellular Proto-oncogenes (such as c-myc and c-fos). It is highly likely that the activation of such normal genes or proto-oncogenes underlies the Physiological effects of growth factors.