Kindlin-1 controls Wnt and TGF-β availability to regulate cutaneous stem cell proliferation

Abstract

Kindlin-1 is an integrin tail binding protein that controls integrin activation. Mutations in the FERMT-1 gene lead to Kindler Syndrome in man, which is characterized by skin blistering, premature skin ageing and skin cancer of unknown etiology. Here we show that loss of Kindlin-1 in mouse keratinocytes recapitulates Kindler Syndrome, and in addition produces enlarged and hyperactive stem cell compartments, which lead to hyperthickened epidermis, ectopic hair follicle development and increased skin tumor susceptibility. Mechanistically, Kindlin-1 controls keratinocyte adhesion through β1-class integrins and proliferation and differentiation of cutaneous epithelial stem cells by promoting αvβ6 integrin-mediated TGFβ activation and by inhibiting Wnt-β-catenin signaling through an integrin-independent regulation of Wnt ligand expression. Our findings assign Kindlin-1 the novel and essential task to control cutaneous epithelial stem cell homeostasis by balancing TGFβ mediated growth inhibitory and Wnt-β-catenin mediated growth-promoting signals.

The kindlin family: functions, signaling properties and implications for human disease

“…However, mice that lack kindlin-1 expression developed additional defects, including aberrant HF cycles and hair development, enlarged SC compartments and cutaneous SC numbers that concomitantly decreased with age, elevated cutaneous SC proliferation and an increased susceptibility to develop skin tumors. None of these defects were apparent in mice that lack β1 integrins or express a kindlinbinding-deficient β1 integrin Rognoni et al, 2014;Frank et al, 2005).…”

“…Intriguingly, colony-forming efficiency assays of serially cultured primary keratinocytes that had been isolated from KS patients indicated accelerated depletion and premature senescence of SCs, suggesting that, similar to those mice that lack kindlin-1 in keratinocytes (Rognoni et al, 2014), the enhanced SC proliferation eventually leads to SC exhaustion, which is accompanied by a loss of SC-marker expression in the patient skin (Lai-Cheong et al, 2009;Piccinni et al, 2013). Two main defects have been identified in the KS mouse model that contribute to the hyperproliferation of Box 1.…”

“…Two main defects have been identified in the KS mouse model that contribute to the hyperproliferation of Box 1. Integrin-binding specificity of kindlins By using pull-down assays with β-integrin-tail peptides, kindlin-1 has been shown to bind β1, β3 and β6 integrins (Bandyopadhyay et al, 2012;Rognoni et al, 2014;Harburger et al, 2009), and kindlin-2 and -3 to bind β1-, β2-and β3-integrin tails (Böttcher et al, 2012;Bledzka et al, 2012;Harburger et al, 2009;Montanez et al, 2008;Moser et al, 2009aMoser et al, , 2008Ma et al, 2008) at their distal NxxY motifs and adjacent threonine and/or serine residues. Mutational analysis in the kindlin F3 subdomain revealed that a conserved (Q)W motif is essential for binding integrin tails (Fitzpatrick et al, 2014;Harburger et al, 2009;Moser et al, 2009aMoser et al, , 2008Rognoni et al, 2014).…”

The role of the microenvironment on the fate of adult stem cells

“…In addition, in a cutaneous epithelial SC microenvironment, Kindlin-1 can trigger integrin to regulate the proliferation and differentiation of cutaneous epithelial SCs by mediating transforming growth factor-β (TGF-β) activation and inhibiting Wnt/β-catenin signaling. This occurs through the integrin-independent regulation of Wnt ligand expression that controls SC quiescence and proliferation [28]. The mechanical properties of the ECM are determined by a network of collagen, fibronectin and fibrin fibrils differing in length and stiffness.…”

Traction forces mediated by integrin signaling are necessary for definitive endoderm specification

“…7, right). Other integrin-associated proteins, such as kindlin and integrin-linked kinase, have been proposed as regulators of TGF-β signaling (Boo and Dagnino, 2013;Rognoni et al, 2014), suggesting that parallel integrin signaling pathways could also be regulating definitive endoderm induction. Taken together, these results suggest that integrin signaling might regulate soluble signaling pathways throughout development and could be an important tool for directing ESC differentiation.…”