title: Kindlin-1 Is required for RhoGTPase-mediated lamellipodia formation in keratinocytes.
abstract: Kindlin-1 is an epithelial-specific member of the novel kindlin protein family, which are regulators of integrin functions. Mutations in the gene that encodes Kindlin-1, FERMT1 (KIND1), cause the Kindler syndrome (KS), a human disorder characterized by mucocutaneous fragility, progressive skin atrophy, ulcerative colitis, photosensitivity, and propensity to skin cancer. Our previous studies indicated that loss of kindlin-1 resulted in abnormalities associated with integrin functions, such as adhesion, proliferation, polarization, and motility of epidermal cells. Here, we disclosed novel FERMT1 mutations in KS and used them, in combination with small-interfering RNA, protein, and imaging studies, to uncover new functions for kindlin-1 in keratinocytes and to discern the molecular pathology of KS. We show that kindlin-1 forms molecular complexes with beta1 integrin, alpha-actinin, migfilin, and focal adhesion kinase and regulates cell shape and migration by controlling lamellipodia formation. Kindlin-1 governs these processes by signaling via Rho family GTPases, and it is required to maintain the pool of GTP-bound, active Rac1, RhoA and Cdc42, and the phosphorylation of their downstream effectors p21-activated kinase 1, LIM kinase, and cofilin. Loss of these kindlin-1 functions forms the biological basis for the epithelial cell fragility and atrophy in the pathology of KS.
authors.affiliation: Department of Dermatology, University Medical Center Freiburg, Freiburg 79104, Germany.
authors.forename: Cristina
authors.initials: C
authors.lastname: Has
authors.forename: Corinna
authors.initials: C
authors.lastname: Herz
authors.forename: Elena
authors.initials: E
authors.lastname: Zimina
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Qu
authors.forename: Yinghong
authors.initials: Y
authors.lastname: He
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Zhang
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Wen
authors.forename: Yannick
authors.initials: Y
authors.lastname: Gache
authors.forename: Monique
authors.initials: M
authors.lastname: Aumailley
authors.forename: Leena
authors.initials: L
authors.lastname: Bruckner-Tuderman
mesh_terms: D000015:Abnormalities, Multiple / Q000201:enzymology / Q000473:pathology; D000328:Adult; D002461:Cell Line, Transformed; D002465:Cell Movement; D048430:Cell Shape; D002648:Child; D004789:Enzyme Activation; D022001:Focal Adhesions / Q000201:enzymology; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D008954:Models, Biological; D009092:Mucous Membrane / Q000002:abnormalities / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding; D011554:Pseudopodia / Q000201:enzymology*; D034741:RNA, Small Interfering / Q000378:metabolism; D012868:Skin Abnormalities / Q000201:enzymology / Q000473:pathology; D013577:Syndrome; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C475301:FERMT1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D006160:Guanosine Triphosphate; D020741:rho GTP-Binding Proteins