Xiaojia (Sasha) Guo, PhD

We have shown that ESDN down-regulation by RNA interference significantly enhanced PDGF-induced VSMC DNA synthesis and migration. This was associated with increased ERK1/2, Src, and PDGF receptor (PDGFR) phosphorylation, without altering total PDGFR expression levels. In binding assays, ESDN down-regulation significantly increased 125I-PDGF maximum binding (Bmax) to PDGF receptors on VSMCs without altering the binding constant (Kd), raising the possibility that ESDN regulates PDGFR processing. ESDN down-regulation significantly reduced ligand-induced PDGFR ubiquitination. This was associated with a significant reduction in the expression level of c-Cbl, an E3 ubiquitin ligase that ubiquitinylates PDGFR. Thus, ESDN modulates PDGF signaling in VSMCs via regulation ofPDGFRsurface levels. The ESDN effect is mediated, at least in part, through effects on PDGFR ubiquitination.

Continued detailed analyses of the involvement of ESDN in the regulation of RTK-driven pathologies is thus predicted to pave the way for therapeutic strategy for vascular diseases and other diseases involving RTK-driven tissue remodeling.