PDGF Signaling

Platelet-derived growth factor (PDGF) refers to a family of dimeric isoforms that are important for growth, survival and function especially in connective tissue. Four different PDGF chains have been identified - the classical PDGF-A and PDGF-B and the more recent PDGF-C and PDGF-D isoforms. These isoforms that occur as homodimers or heterodimers (PDGF-AA, AB, BB, CC and DD) exert their effects by differential binding to two receptor tyrosine kinases. Binding of PDGF induces dimerization and autophosphorylation of the tyrosine kinase receptors. Depending on the PDGF isoform involved, homo or heterodimers of the receptor are formed.Receptor phosphorylation triggers the recruitment of several Src homology 2 (SH2) domain-containing signaling proteins, including phospholipase C gamma1 (PLCγ1), phosphoinositide 3-kinase (PI3K), SH2 domain-containing protein tyrosine phosphatase-2 (SHP2), growth factor receptor-bound protein 2 (GRB2), (Src homology 2 domain containing) transforming protein (SHC)and SRC kinase to the receptor. The activation of RAS protein via SHC and GRB2 triggers the Mitogen activated protein kinase (MAPK) pathway, leading to the activation of transfactors like c-JUN and ELK1 leading ultimately to changes in gene expression. PDGF activation of Janus kinase (JAK), SRC kinase and double-stranded RNA (dsRNA)-activated protein kinase (PKR) leads to the activation of Signal transducers and activators of transcription (STAT1 and 3) which result in transcriptional activation of genes involved in cell proliferation and survival. PDGF activation of sphingosine kinase (SPHK)results in mitogenesis, where as activation of Abelson kinase (c-ABL) results in membrane ruffling and chemotaxis. Thus PDGF signaling results in diverse cellular effects.PDGF signaling can be regulated by factors like Low molecular weight phosphotyrosine phosphatase (LMW-PTP) and Caveolin (CAV).This Pathway highlights some key components of PDGF signaling.