Mechanism of action of platelet-derived growth factor.

More than 20 years ago, platelet-derived growth factor (PDGF) was identified and later purified. Through recent years of intense research, a large body of information has been collected on how PDGF transduces its biological effects to responding cells. Two homologous receptors, the PDGF alpha- and beta-receptors, have been identified, which are receptor tyrosine kinases. Binding of PDGF leads to activation of the kinase and autophosphorylation. Particularly in the PDGF beta-receptor, a considerable number of autophosphorylation sites have been identified, which allow for physical interaction with signal transduction molecules. The signal transduction molecules are often enzymes, which undergo activity changes in conjunction with binding to the receptor. Other signal transduction molecules function as adaptors, which can couple to subunits equipped with catalytic activity. Through the activity changes of inherent or directly coupled catalytic activities, a signal is propagated, which ultimately results in a cellular response. PDGF is known to induce migration, proliferation and differentiation of different cells types. An array of signal transduction molecules has been shown to interact with the PDGF beta-receptor; several appear to contribute to the generation of the proliferative response, indicating the existence of parallel pathways for this response, which are utilized by many different growth factor receptors. Migration of cells towards PDGF appears to be more strictly dependent on activation of phosphatidylinositol 3' kinase. Interestingly, the PDGF alpha-receptor emits negative signals that inhibit simultaneous positive signals for migration induced by this receptor, or by other receptors, such as the PDGF beta-receptor. Virtually nothing is known about signal transduction initiated by PDGF, which generates differentiation responses. Since PDGF appears to play a role in different physiological and pathological processes, it is important to continue delineation of signal transduction pathways initiated through activation of the PDGF receptors.