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 PDGF Pathway

The platelet-derived growth factor (PDGF) network supports a variety of cell processes including proliferation, survival, movement, deposition of extracellular matrix (ECM) and tissue remodeling. PDGFs drive mesenchymal proliferation in early tissues such as testis, kidney, intestine, skin and lung. PDGFs support vascular development and angiogenesis in a variety of organs. For instance, PDGF-BB/PDGFR-BB support angiogenesis at the level of mural cell development, vascular smooth muscle cells (VSMC) and pericytes. The PDGF family is composed of two classical, PDGF-A and PDGF-B and two novel, PDGF-C and PDGF-D, growth factors. These factors interact with two receptors, PDGFRalpha (PDGFRα) and PDGFRbeta (PDGFRβ), with cell and context specific affinities and specificities. PDGF-A and PDGFRα are associated with embryogenesis, CNS and organ development, whereas PDGF-B and PDGFRβ are involved with the development of vasculature, especially with vascular smooth muscle cells. PDGF-C has been linked to normal development of the heart, ear, central nervous system, kidney and palatogenesis, palate formation via embryonic palatal mesenchymal (MEPM) cells. PDGF-D is involved with development of the kidney, lung, eye and brain. Active PDGFs are homodimers, PDGF-AA, PDGF-BB, PDGF-CC, PDGF-DD, and the heterodimer PDGF-AB. The classical PDGFs can bind directly to their surface receptors, whereas the novel PDGFs must be activated by limited proteolysis by an extracellular protease before they bind to their receptors. Tissue plasminogen activator (tPA) is a potent activator of PDGF-CC. Ligand binding induces the PDGF receptors to dimerize into homo- (AA or BB) or heterodimers (AB) and to autophosphorylate. These activated receptors transduce signaling by activating pathways common to both receptor tyrosine kinases (RTK). Alpha and beta receptors interact with Src, PI3K, SHP2, Shc, and PLCgamma. Src is a non-receptor tyrosine kinase that activates downstream effectors in a cell and context specific manner. Phosphoinositol-3 kinase (PI-3K) activates Akt/PKB, which promotes cell survival, protein synthesis and cell cycle progression. Phospholipase Cgamma signals the elevation of internal calcium and the activation of various protein kinase Cs (PKC). The alpha and beta receptors differentiate signaling to the MAP-kinase, JNK/SAPK and ERK, pathways via their use of different signaling interfaces. Alpha receptor and beta receptors signal the JNK/SAPK pathways using Crk and Nck, respectively. Both receptors signal the Ras/Raf/MEK/ERK pathway via Shc, but the beta receptor also involves SYP (SHPTP2) and Grb2/7 and the negative regulator RasGAP. The PDGF receptors also activate the transcription factors STAT-1, STAT-3 and STAT-5 via mechanisms that involve Src and JAK kinases.