| First Author | Seltmann K | Year | 2015 |
| Journal | J Invest Dermatol | Volume | 135 |
| Issue | 6 | Pages | 1609-1620 |
| PubMed ID | 25668239 | Mgi Jnum | J:221063 |
| Mgi Id | MGI:5637878 | Doi | 10.1038/jid.2015.46 |
| Citation | Seltmann K, et al. (2015) Keratins Stabilize Hemidesmosomes through Regulation of beta4-Integrin Turnover. J Invest Dermatol 135(6):1609-20 |
| abstractText | Epidermal integrity and wound healing depend on remodeling of cell-matrix contacts including hemidesmosomes. Mutations in beta4-integrin and plectin lead to severe epidermolysis bullosa (EB). Whether mutations in keratins K5 or K14, which cause EB simplex, also compromise cell-matrix adhesion through altering hemidesmosomal components is not well investigated. In particular, the dependence of beta4-integrin endocytosis and turnover on keratins remains incompletely understood. Here, we show that the absence of keratins causes loss of plectin-beta4-integrin interaction and elevated beta4-integrin phosphorylation at Ser1354 and Ser1362. This triggered a caveolin-dependent endocytosis of beta4-integrin but not of other integrins through Rab5 and Rab11 compartments in keratinocytes. Expressing a phospho-deficient beta4-integrin mutant reduces beta4-integrin endocytosis and rescues plectin localization in keratin-free cells. beta4-integrin phosphorylation in the absence of keratins resulted from elevated Erk1/2 activity downstream of increased EGFR and PKCalpha signaling. Further, increased Erk1/2 phosphorylation and altered plectin localization occur in keratin-deficient mouse epidermis in vivo. Strikingly, expression of the K14-R125P EBS mutant also resulted in plectin mislocalization and elevated beta4-integrin turnover, suggesting disease relevance. Our data underscore a major role of keratins in controlling beta4-integrin endocytosis involving a plectin-Erk1/2-dependent mechanism relevant for epidermal differentiation and pathogenesis. |
