A Fibronectin Peptide Redirects PDGF-BB/PDGFR Complexes to Macropinocytosis-Like Internalization and Augments PDGF-BB Survival Signals

Abstract

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.

Nanoparticles and nanofibers for topical drug delivery

“…Systemic and topical administration of ketanserin, a selective S2-serotonin antagonist, accelerated wound healing of diabetic foot ulcers [168,169]. Macri et al incorporated a fibronectin-derived peptide (P12) that holds promise in the treatment of burns [170] into tyrosine-derived polycarbonates using a standard electrospinning setup. It was shown that both polymer composition and drug loading significantly affected in vitro drug release [142].…”

Fibronectin Interaction and Enhancement of Growth Factors: Importance for Wound Healing

“…31 Moreover, P12 alters PDGF-BB/PDGF receptor (PDGFR) endocytosis and survival signals, that is, Akt phorphorylation. 41 Results suggested that P12 shifts cell trafficking of PDGF-BB/PDGFR from clathrin-mediated (Fig. 3a-c) dynamin-dependent endocytosis (Fig.…”

“…3d) to a macropinocytosis-like pathway and thereby prolongs PDGFR signaling. 42 Hybrid FN-and GF-receptor adhesion complexes that integrate signaling FN-integrin interactions play a key role in cellular behaviors, including cell migration, vascular development, and cohesion. One of the most studied sequences in FN is Arg-Gly-Asp (RGD), which is located in FNIII 10 .…”

Regenerative Medicine: Charting a New Course in Wound Healing

“…An example of this is a fibronectin peptide known as P12, which binds platelet-derived growth factor BB (PDGF-BB) and enhances its effects on burn healing and fibroblast survival under stress. 49 Evidence suggests that the mechanism by which P12 acts is to slow internalization of the PDGF-receptor complex by redirecting it from the clathrin-dependent endocytic pathway to a macropinocytosis-like pathway. 49 …”

“…49 Evidence suggests that the mechanism by which P12 acts is to slow internalization of the PDGF-receptor complex by redirecting it from the clathrin-dependent endocytic pathway to a macropinocytosis-like pathway. 49 …”