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Abstract:
PINCH-1 is a LIM-only domain protein that forms a ternary complex with
integrin-linked kinase (ILK) and parvin (to form the IPP complex)
downstream of integrins. Here, we demonstrate that PINCH-1 (also known
as Lims1) gene ablation in the epidermis of mice caused epidermal
detachment from the basement membrane, epidermal hyperthickening and
progressive hair loss. PINCH-1-deficient keratinocytes also displayed
profound adhesion, spreading and migration defects in vitro that were
substantially more severe than those of ILK-deficient keratinocytes
indicating that PINCH-1 also exerts functions in an ILK-independent
manner. By isolating the PINCH-1 interactome, the LIM-domain-containing
and actin-binding protein epithelial protein lost in neoplasm (EPLIN,
also known as LIMA1) was identified as a new PINCH-1-associated protein.
EPLIN localized, in a PINCH-1-dependent manner, to integrin adhesion
sites of keratinocytes in vivo and in vitro and its depletion severely
attenuated keratinocyte spreading and migration on collagen and
fibronectin without affecting PINCH-1 levels in focal adhesions. Given
that the low PINCH-1 levels in ILK-deficient keratinocytes were
sufficient to recruit EPLIN to integrin adhesions, our findings suggest
that PINCH-1 regulates integrin-mediated adhesion of keratinocytes
through the interactions with ILK as well as EPLIN.
