Role of Kindlin-2 in Fibroblast Functions: Implications for Wound Healing

Abstract

Kindlins are a protein family that regulates cell-matrix interactions. Although kindlin-2 is known to be essential for the early developmental processes, its role in the homeostasis of adult tissues has remained elusive. In this study, we used new domain-specific antibodies and small interfering RNA technology to uncover physiological functions of kindlin-2 in human dermal fibroblasts in vitro and in adult skin in situ. In primary dermal fibroblasts, kindlin-2 is essential for the integrin clustering and activation, and it regulates cell adhesion and directed migration by guiding formation and maturation of focal adhesions (FAs) and organization of the cytoskeleton. These functions are linked to the transmission of mechanical cues between cells and their microenvironment, typically in processes wherein fibroblasts differentiate to myofibroblasts under mechanical tension. In concert, kindlin-2 was shown to be required for the stabilization and maturation of FAs and stress fibers in activated fibroblasts and myofibroblasts. These findings implicated that in physiological wound closure and tissue repair, the prediction was validated by strong upregulation of kindlin-2 in contractile myofibroblasts during middle stages of wound healing in human skin. Taken together, the data reveal a physiological role for kindlin-2 in skin fibroblasts under normal steady-state conditions and during tissue regeneration.

Uncovering functional differences between kindlin-1 and kindlin-2 in keratinocytes

“…The average area of the scrambled knockdown cells was 3183 mm 2 , whereas the area of the kindlin-2-knockdown cells was 2214 mm 2 . The reduction in cell spreading seen in kindlin-2-knockdown cells is in agreement with recent data on spreading of kindlin-2-knockdown fibroblasts (He et al, 2011b). We next looked at the localization of b1 integrin and kindlin-2 in scrambled and kindlin-2-knockdown cells.…”

Kindlin-2 interacts with β-catenin and YB-1 to enhanceEGFRtranscription during glioma progression

“…The major signaling pathways downstream of EGFR include the MEK-ERK, PI3K-AKT, PLC-PKC, and STAT pathways [38]. EGF can stimulate Kindlin-2 expression at both the mRNA and protein levels through the EGFR signaling pathway [17, 39]. The Kindlin-2/integrin β1/AKT axis was shown to contribute to esophageal squamous cell cancer, while the Kindlin-2/EGFR/AKT axis was shown to be involved in breast cancer [39–40].…”

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

“…The role of kindlin-2 in dermal fibroblasts was analyzed in healing wounds. Kindlin-2 becomes highly expressed in activated myofibroblasts, where it regulates FA formation, the organization of α-smooth muscle actin into stress fibers and the transmission of force (He et al, 2011b).…”