Signal transduction by the PDGF receptors.
The three isoforms of PDGF bind with different affinities to two related tyrosine kinase receptors, denoted the PDGF alpha- and beta-receptors. Ligand binding induces receptor dimerization, creating receptor homo- or heterodimers. Dimerization is accompanied by, and might be a prerequisite for, receptor autophosphorylation and kinase activation. Receptor autophosphorylation serves to regulate the kinase activity and to create binding sites on the receptor molecule for downstream signalling components. The activities of the signalling components are ultimately manifested as specific biological responses. All the currently described PDGF receptor-binding components, e.g. phospholipase C-gamma, members of the src family of cytoplasmic tyrosine kinases, the rasGT-Pase activating protein and p85, the regulatory subunit of phosphatidylinositol 3' kinase, contain a conserved src homology 2-domain, through which the association with the receptor takes place. The receptor-binding components appear to either possess an intrinsic enzymatic activity, or they function as adaptors, which may complex with catalytically active components. For most receptor-binding components, there is insufficient understanding of how binding to the receptor affects the catalytic function. Certain of these components become tyrosine-phosphorylated, i.e. they are substrates for the receptor tyrosine kinase. Moreover, the change in subcellular localization, which most of the receptor binding components undergo in conjunction with receptor binding, could play a critical role. The current efforts of many laboratories are aimed at delineating different PDGF receptor signal transduction pathways and what roles the different receptor-binding components play in the establishment of these pathways.
Claesson-Welsh
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Ludwig Institute for Cancer Research, Biomedical Center, Uppsala, Sweden.
D000595:Amino Acid Sequence; D000818:Animals; D020690:GTPase-Activating Proteins; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011506:Proteins / Q000502:physiology; D017479:Receptors, Platelet-Derived Growth Factor / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D020690:GTPase-Activating Proteins; D008024:Ligands; D011506:Proteins; D017479:Receptors, Platelet-Derived Growth Factor