Avtor/Urednik		Seltmann, Kristin; Cheng, Fang; Wiche, Gerhard; Eriksson, John E.; Magin, Thomas M.
Naslov		Keratins stabilize hemidesmosomes through regulation of [beta]4-Integrin turnover
Tip		članek
Vol. in št.		Letnik 135, št. 6
Leto izdaje		2015
Obseg		str. 1609-1620
ISSN		0022-202X - The Journal of investigative dermatology
Jezik		eng
Abstrakt		Epidermal integrity and wound healing depend on remodeling of cell-matrix contacts including hemidesmosomes. Mutations in [beta]4-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 [beta]4-integrin endocytosis and turnover on keratins remains incompletely understood. Here, we show that the absence of keratins causes loss of plectin-[beta]4-integrin interaction and elevated [beta]4-integrin phosphorylation at Ser1354 and Ser1362. This triggered a caveolin-dependent endocytosis of [beta]4-integrin but not of other integrins through Rab5 and Rab11 compartments in keratinocytes. Expressing a phospho-deficient [beta]4-integrin mutant reduces [beta]4-integrin endocytosis and rescues plectin localization in keratin-free cells. [beta]4-integrin phosphorylation in the absence of keratins resulted from elevated Erk1/2 activity downstream of increased EGFR and PKC[alpha] 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 [beta]4-integrin turnover, suggesting disease relevance. Our data underscore a major role of keratins in controlling [beta]4-integrin endocytosis involving a plectin-Erk1/2-dependent mechanism relevant for epidermal differentiation and pathogenesis.
Proste vsebinske oznake		celični matriks beta4-integrin mutacije cell-matrix beta4-integrin mutations