Krüppel-like Factor 5 Controls Keratinocyte Migration via the Integrin-linked Kinase

Abstract

Migration of epithelial cells is critical for normal homeostasis in gut and skin, but the factors regulating this process are not completely understood. The zinc finger transcription factor Klf5 (IKLF; BTEB2) is highly expressed in proliferating cells of esophagus, skin, and other organs. We hypothesized that Klf5 regulates keratinocyte migration via the integrin-linked kinase (ILK), which, like Klf5, is localized to basal keratinocytes. We stably transduced mouse primary esophageal keratinocytes to overexpress Klf5 or small interfering RNA against Klf5. Klf5 overexpression in keratinocytes increased migration and correlated directly with ILK expression and activation. ILK expression restored migratory capacity in keratinocytes with suppression of Klf5, whereas ILK small interfering RNA blocked the increased migration resulting from Klf5 overexpression. By chromatin immunoprecipitation, electromobility shift assay, and luciferase reporter assays, we confirmed that ILK was a direct target for Klf5. In addition, Klf5 induced the activation of the ILK targets Cdc42 and myosin light chain, which are critical for cell migration and motility but not Rac1, AKT, or GSK3␤.Overall, these results demonstrate that Klf5 is a key regulator of cell migration via ILK and provide new insight into the regulation of epithelial cell migration.Spatial separation of proliferating and differentiating cells is a common theme throughout the epithelia of the luminal gastrointestinal tract, the skin, and several other organs (1-3). Migration of cells within these epithelia is critical for differentiation and normal homeostasis. A number of different epithelial types are found throughout the human body, of which the stratified squamous epithelium, which lines the esophagus, skin, oral cavity, and several other organs, is the most common. In stratified squamous epithelia, the basal layer is composed of both epithelial stem cells and transit-amplifying cells (4 -6). These transit-amplifying cells are partially committed, rapidly proliferating cells that originate from asymmetric divisions of the stem cells and then migrate, both within the basal layer and from the basal layer, toward the surface (7,8). While migrating within the basal layer, the transit-amplifying cells undergo several rounds of rapid proliferation and clonal expansion. Keratinocytes then undergo additional differentiation during migration through the suprabasal and superficial layers, losing their proliferative capacity.A number of pathways are known to be critical for keratinocyte migration (reviewed in Ref. 9). Interactions of keratinocytes with the extracellular matrix are especially important for migration, and the integrins and the integrin-linked kinase (ILK) 2 play key roles in transducing signals from the extracellular matrix. ILK is an adaptor protein that couples integrins and growth factor receptors to a variety of downstream signaling events, influencing cell adhesion, proliferation, migration, differentiation, and survival (10 -12). ILK binds to the cytoplasmic...

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

“…Interestingly, a connection between KLF5 expression and activation of the integrin-linked kinase was recently shown in a keratinocyte model, suggesting that cell contact could influence KLF5 expression, thus mediating cell migration and invasiveness (28). We therefore investigated whether cell density modulates KLF5 expression in pancreatic cancer cells.…”

KLF5 Activates MicroRNA 200 Transcription To Maintain Epithelial Characteristics and Prevent Induced Epithelial-Mesenchymal Transition in Epithelial Cells

“…Opposite the inhibition of cell migration by KLF5 in HaCaT cells observed in this study (Figs. 2B, 3B, and 8F), KLF5 could also promote cell migration in other cell types (6,9,10), including mouse primary esophageal keratinocytes, where Klf5 appears to promote cell migration by inducing the expression of integrin-linked kinase (ILK) (10); bronchial smooth muscle cells, where interleukin-8-induced cell migration could be blocked by the knockdown of KLF5 (9); and intestinal epithelial cells, where deletion of Klf5 impairs the migration of Paneth cells (6). Therefore, it is possible that the role of KLF5 in EMT is context dependent.…”

“…It mediates or regulates diverse cellular processes, including proliferation, cell cycle, apoptosis, differentiation, and migration (8). Cellular migration, for example, appears to be regulated by KLF5 in a context-dependent manner (6,9,10), as KLF5 promotes cell migration in mouse primary esophageal keratinocytes by inducing the integrin-linked kinase (ILK) (10). Loss of Klf5 could drive invasive progression of human squamous cell cancer in the context of p53 ablation (11).…”

Overexpression of WWP1 is associated with the estrogen receptor and insulin‐like growth factor receptor 1 in breast carcinoma

“…KLF5 has been shown to promote migration. 36 RunX2 has long been associated with breast cancer metastasis by activating expression of bone matrix and adhesion proteins, matrix metalloproteinases and angiogenic factors. 37 Whether WWP1 truly suppresses breast cancer metastasis through inhibiting the TGFb pathway and transcription factors should be addressed in future studies.…”