Platelet-Derived Growth Factor (PDGF) signaling transduction controls cell proliferation, differentiation, migration, and survival via ligand-specific activation. PDGF signaling consists of four ligands, PDGFA, PDGFB, PDGFC, PDGFD, and two receptors, PDGF receptor alpha, also known as PDGFRA / CD140a, and PDGF receptor beta, also known as PDGFRB / CD140b. PDGFRA and PDGFRB belong to the family of transmembrane receptor tyrosine kinases (RTKs).
All PDGFs function as secreted, disulphide-linked homodimers (PDGF-AA, PDGF-BB, PDGF-CC and PDGFDD), but only PDGFA and B can form functional heterodimers (PDGF-AB). As a crucial component in PDGF signaling, PDGFRs can also form three dimeric isoforms: homodimeric PDGFRAA and BB and heterodimeric PDGFRAB. PDGFs bind to PDGFRs with different affinities.
Dimerization is the key event in PDGF receptor activation as it allows for receptor autophosphorylation on tyrosine residues in the intracellular domain. Autophosphorylation activates the receptor kinase and provides docking sites for downstream signaling molecules. Three well-characterized signaling pathways are Ras-MAPK, PI3K, and PLC-which are known to be involved in multiple cellular and developmental responses.
PDGFRs connect to Ras-MAPK mainly through the adaptor proteins Grb2. Grb2 binds the activated PDGFR through its SH2 domain and complexes Sos1 through its SH3 domains. Sos1 in turn activates Ras, leading to downstream activation of Raf-1 and the MAPK cascade. MAPK signaling activates gene transcription, leading to stimulation of cell growth, differentiation, and migration (Figure 1).
PLC-γ binds PDGFRs, which results in its activation through phosphorylation. PLC-γ activation leads to mobilization of intracellular calcium ions and the activation of PKC. The effects of PDGFR-mediated PLC-γ activation include stimulation of cell growth and motility. Activation of the PI3K pathway by PDGFRs promotes actin reorganization, directed cell movements, stimulation of cell growth, and inhibition of apoptosis.
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