Increased abundance of Cbl E3 ligases alters PDGFR signaling in recessive dystrophic epidermolysis bullosa

• Published in: Matrix biology 2021-09, Vol.103-104, p.58-73
• Main Authors: Martínez-Martínez, Esther, Tölle, Regine, Donauer, Julia, Gretzmeier, Christine, Bruckner-Tuderman, Leena, Dengjel, Jörn
• Format: Article
• Language: English
• Subjects: AKT protein; CBL; Cbl protein; Collagen; Collagen Type VII; Dystrophic epidermolysis bullosa; Epidermolysis bullosa; Epidermolysis Bullosa Dystrophica - genetics; Fibrils; Fibroblast; Fibroblasts; Fibrosis; Growth factor; Growth factors; Humans; Internalization; Intracellular signalling; MAP kinase; Mass spectrometry; mRNA; PDGFR; Phosphoproteomics; Phosphorylation; Platelet-derived growth factor; Receptor tyrosine kinase; Receptors, Platelet-Derived Growth Factor - genetics; Signal transduction; Tyrosine phosphorylation; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitination; Wound Healing
• ISSN: 0945-053X; 1569-1802
• DOI: 10.1016/j.matbio.2021.10.004

•Using a phosphoproteomic screen, we identify dysregulation in growth factor receptor signaling in RDEB.•Via overactivation of TGFβ signaling, loss of collagen VII leads to increased protein abundance and activity of Cbl E3 ubiquitin ligases.•Elevated activity of Cbl ligases leads to increased PDGFR ubiquitination, internalization, and degradation.•Compared to normal human skin fibroblasts, RDEB fibroblasts exhibit a reduced potential to migrate and proliferate upon growth factor stimulation. 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.