ABSTRACT
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 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 contribute to impaired dermal wound healing in RDEB.
Competing Interest Statement
The authors have declared no competing interest.
Abbreviations
- NHF
- normal human fibroblast
- RDEB
- recessive dystrophic epidermolysis bullosa
- MS
- mass spectrometry
- LC
- liquid chromatography
- IP
- immunoprecipitation
- PDGFR
- platelet-derived growth factor receptor
- BrdU
- bromodeoxyuridine
- TGFβ
- transforming growth factor β