Journal
MATRIX BIOLOGY
Volume 103, Issue -, Pages 58-73Publisher
ELSEVIER
DOI: 10.1016/j.matbio.2021.10.004
Keywords
Fibroblast; Growth factor; Mass spectrometry; Receptor tyrosine kinase; Tyrosine phosphorylation; Ubiquitination; Phosphoproteomics; CBL; PDGFR
Categories
Funding
- German Research Foundation (DFG) [DE 1757/32]
- Swiss National Science Foundation [177088]
- Innosuisse Program [29588.1]
- University of Fribourg
- Canton of Fribourg
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Loss of collagen VII in recessive dystrophic epidermolysis bullosa (RDEB) affects PDGFR signaling and intracellular pathways, leading to impaired wound healing. Elevated TGF beta signaling in RDEB contributes to attenuated response to growth factors, resulting in impaired dermal wound healing.
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 TGF beta 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 TGF beta signaling leads to an attenuated response to growth factors, which contributes to impaired dermal wound healing in RDEB. (c) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license(http://creativecommons.org/licenses/by/4.0/)
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