In recessive dystrophic epidermolysis bullosa (RDEB), loss of collagen VII, the main component of anchoring fibrils critical for epidermal-dermal cohesion, affects several intracellular signaling pathways and leads to impaired wound healing and fibrosis. In skin fibroblasts, wound healing is also affected by platelet-derived growth factor receptor (PDGFR) signaling. To study a potential effect of loss of collagen VII on PDGFR signaling we performed unbiased disease phosphoproteomics. Whereas RDEB fibroblasts exhibited an overall weaker response to PDGF, Cbl E3 ubiquitin ligases, negative regulators of growth factor signaling, were stronger phosphorylated. This increase in phosphorylation was linked to higher Cbl mRNA and protein levels due to increased TGFβ signaling in RDEB. In turn, increased Cbl levels led to increased PDGFR ubiquitination, internalization, and degradation negatively affecting MAPK and AKT downstream signaling pathways. Thus, our results indicate that elevated TGFβ signaling leads to an attenuated response to growth factors, which contributes to impaired dermal wound healing in RDEB.

在隐性营养不良性大疱性表皮松解症 (RDEB) 中，胶原蛋白 VII 的损失是锚定原纤维的主要成分，对表皮 - 真皮的凝聚力至关重要，会影响几种细胞内信号通路并导致伤口愈合和纤维化受损。在皮肤成纤维细胞中，伤口愈合也受到血小板衍生生长因子受体 (PDGFR) 信号传导的影响。为了研究胶原蛋白 VII 损失对 PDGFR 信号传导的潜在影响，我们进行了无偏疾病磷酸蛋白质组学。虽然 RDEB 成纤维细胞对 PDGF 的反应总体较弱，但 Cbl E3 泛素连接酶（生长因子信号传导的负调节剂）磷酸化更强。由于 RDEB 中 TGFβ 信号的增加，这种磷酸化的增加与更高的 Cbl mRNA 和蛋白质水平有关。反过来，增加的 Cbl 水平导致增加 PDGFR 泛素化，内化和降解对 MAPK 和 AKT 下游信号通路产生负面影响。因此，我们的结果表明，升高的 TGFβ 信号传导导致对生长因子的反应减弱，这导致 RDEB 中皮肤伤口愈合受损。