A Unique Autophosphorylation Site in the Platelet‐Derived Growth Factor α Receptor from a Heterodimeric Receptor Complex

Abstract

The platelet-derived growth factor (PDGF) a and p receptors undergo dimerization as a consequence of ligand binding. Depending on the PDGF isoform (PDGF-AA, -AB or -BB), homodimers or heterodimers of receptors are formed. In this study, we have used transfected porcine aortic endothelial cells, coexpressing cDNAs for the a receptor and the p receptor at comparable levels, to investigate the properties of the up-heterodimeric receptor complex. PDGF-AB, which mainly induced ap-heterodimeric complexes, was the most efficient isoform for stimulating mitogenicity. Actin reorganization, in the form of circular membrane ruffling and chemotaxis, was induced by PDGF-AB and PDGF-BB, but not by PDGF-AA, thus indicating that the p receptor in the homodimeric or heterodimeric configuration was required for induction of motility responses. The molecular basis for the apparent receptor dimer-specific properties was examined by analyzing receptor autophosphorylation and phosphorylation of substrates. The a receptor was found to be phosphorylated at an additional tyrosine residue, Tyr754, in the heterodimeric complex as compared to the aa receptor homodimer. Phosphorylation of this tyrosine residue could permit the binding of a specific signal-tranducing protein. A candidate is a 134000-Mr protein, which was shown to associate preferentially with the a receptor in the heterodimeric receptor complex. It is possible that phosphorylated Tyr754 in the a receptor mediates activation of specific signal-tranducing molecules like the 134 000-M, substrate, and thereby initiates signal-tranduction pathways from the ap receptor heterodimer, which are distinct from those initiated via homodimeric receptor complexes.

SHP-2 is involved in heterodimer specific loss of phosphorylation of Tyr771 in the PDGF β-receptor

“…The PDGF-AB isoform has been reported to possess the strongest ability to induce a mitogenic response in cells expressing both a-and b-receptors (Heidaran et al, 1991;Rupp et al, 1994). We have therefore investigated the possible unique features of the heterodimeric PDGF receptor complex compared to the homodimeric complexes, and found that in the heterodimeric complex activation of Ras and Erk2 MAP kinase were stronger and more sustained compared to homodimeric complexes (Ekman et al, 1999).…”

Activation of Growth Factor Receptors in Esophageal Cancer—Implications for Therapy

“…In addition, PDGF-CC and PDGF-DD have been shown to activate ␤-and ␣-receptors, respectively, in cells expressing both receptor types [87][88][89][90]. The PDGF-AB isoform has been reported to possess the strongest ability to induce a mitogenic response in cells expressing both ␣-and ␤-receptors [91,92].…”

PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas

“…PDGFR can form a heterodimeric receptor complex between the a and b receptors (Rupp et al 1994). In addition, PDGFRA and PDGFRB can also form heterodimers with other RTK family members, as demonstrated for FGF-R1 and EGFR, respectively (Saito et al 2001;Faraone et al 2006).…”