Pathological Signaling via Platelet-Derived Growth Factor Receptor α Involves Chronic Activation of Akt and Suppression of p53

Abstract

In contrast to direct activation of platelet-derived growth factor (PDGF) receptor α (PDGFRα) via PDGF, indirect activation via growth factors outside the PDGF family failed to induce dimerization, internalization, and degradation of PDGFRα. Chronically activated, monomeric PDGFRα induced prolonged activation of Akt and suppressed the level of p53. These events were sufficient to promote both cellular responses (proliferation, survival, and contraction) that are intrinsic to proliferative vitreoretinopathy (PVR) and induce the disease itself. This signature signaling pathway appeared to extend beyond PVR since deregulating PDGFRα in ways that promote solid tumors also resulted in chronic activation of Akt and a decline in the level of p53.