A fibronectin peptide redirects PDGF-BB/PDGFR complexes to macropinocytosis-like internalization and augments PDGF-BB survival signals

Growth factor-binding domains identified in various extracellular matrix (ECM) proteins have been shown to regulate growth factor activity in many ways. Recently we identified a fibronectin peptide (P12) that can bind platelet-derived growth factor BB (PDGF-BB) and promote adult human dermal fibroblast (AHDF) survival under stress. In vivo experiments in a porcine burn injury model showed that P12 limited burn injury progression, suggesting an active role in tissue survival. In this report, we explored the molecular mechanism of this peptide in ADHF under nutrient deprivation. Our results showed that P12 acted like some cell penetrating peptides (CPPs) in that it redirected ligand-bound PDGFR from the clathrin-dependent endocytic pathway to a slower, macropinocytosis-like pathway. P12 slowed internalization and degradation of PDGF-BB, augmented its survival signals, and promoted cell survival after nutrient-removal. Our findings demonstrate a mechanism for a potential therapeutic peptide that increases cell and tissue survival by acting as a cofactor to PDGF-BB.