Focal adhesion kinase is required for β-catenin-induced mobilization of epidermal stem cells

Abstract

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that integrates signals downstream of integrin and growth factor activation. Previously, we have shown that skin-specific loss of fak prevents chemically induced skin carcinogenesis in mice following phorbol ester treatment. In this study, we show that skinspecific deletion of fak prevents mobilization of stem cells within the bulge region of the hair follicle, which are the precursors of papillomas following phorbol ester treatment. We also show that phorbol ester treatment results in activation of-catenin within the skin and that FAK is required for β-catenin-induced stem cell mobilization. In addition, inhibition of Src kinase activity, a major binding partner of FAK also prevents stem cell mobilization. We show that FAK is required for the nuclear localization of β-catenin in the skin following phorbol ester treatment and the transcriptional activation of the β-catenin target gene c-Myc. This provides the first evidence of cross-talk between integrin and Wnt signalling pathways in the control of epidermal stem cells and the early events associated with skin carcinogenesis.

Equine Epidermis: A Source of Epithelial-Like Stem/Progenitor Cells with In Vitro and In Vivo Regenerative Capacities

“…For instance, stem cell factor has been reported as an indicator for skin stem cells, despite its expression by mature melanocytes [49]. Other markers, such as CK19 [12] and b-catenin, are expressed not only in skin stem cells [50], but also by differentiated epidermal cells [11]; whereas b-catenin is also present in lymphocytes [51]. In this study, Casein Kinase 2b and Ki67 were used to quantify the number of proliferating [36] epithelial cells [37].…”

Focal adhesion complex proteins in epidermis and squamous cell carcinoma

“…56 Skin-specific loss of FAK also prevented phorbol ester-induced skin carcinogenesis, potentially due to prevention of β-catenin-induced stem cell mobilization in the bulge of the hair follicle. 57 Inhibition of Src, a kinase that intricately associates with FAK at FA complexes also showed the same effect on preventing stem cell mobilization. 57 In other types of carcinomas, FAK signaling has been intricately associated with PI3K/Akt signaling, providing a potential mechanism by which FAK acts to promote tumor growth and progression to malignancy.…”

“…57 Inhibition of Src, a kinase that intricately associates with FAK at FA complexes also showed the same effect on preventing stem cell mobilization. 57 In other types of carcinomas, FAK signaling has been intricately associated with PI3K/Akt signaling, providing a potential mechanism by which FAK acts to promote tumor growth and progression to malignancy. In a neuroblastoma tumor model, treatment with Y15, a FAK inhibitor, or with a FAK siRNA blocks gastrin-releasing peptide receptor (GRP-R)-mediated tumor growth and metastasis to the liver.…”

Integrin signalling regulates YAP and TAZ to control skin homeostasis

“…APC p53 tumour sections from implanted nude mice were obtained from Owen Sansom (The Beatson Institute). K14-Cre Fak fl/fl mice and Src fl/fl , Fyn −/− , Yes −/− mice were obtained from Val Brunton (University of Edinburgh) and were described previously (Marcotte et al, 2012;Ridgway et al, 2012).…”