Osteoblast mineralization requires β1 integrin/ICAP-1–dependent fibronectin deposition

Abstract

ICAP-1 prevents recruitment of kindlin-2 to β1 integrin to control dynamics of fibrillar adhesion sites, fibronectin deposition, and osteoblast mineralization during bone formation.

Nuclear Localization of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP1) Influences β1 Integrin Activation and Recruits Krev/Interaction Trapped-1 (KRIT1) to the Nucleus

“…The Integrin-binding PTB Domain of ICAP1 Is More Effective Than Full-length ICAP1 at Suppressing ␤1 Integrin ActivationConsistent with the role of ICAP1 as a direct inhibitor of ␤1 integrin activation (32)(33)(34)(35), we previously demonstrated that expression of green fluorescent protein (GFP)-tagged ICAP1 PTB domain (ICAP1 residues 49 -200, ICAP1 PTB ) suppresses ␤1 integrin activation and that this requires the formation of a typical PTB domain-ligand interaction between integrin ␤1 and ICAP1 (7). However, ICAP1 contains an additional 48 residues N-terminal to the PTB domain (Fig.…”

“…Collectively, these data indicate that exogenous KRIT1 localization is affected by direct binding to endogenous ICAP1. FEBRUARY 3, 2017 • VOLUME 292 • NUMBER 5 rin activation and thus modulates downstream signaling (32)(33)(34)(35). KRIT1 competes with ␤1 integrin for binding to ICAP1 and hence can reverse ICAP1-mediated integrin ␤1 repression (7).…”

Structural and mechanical functions of integrins

“…For instance, ICAP1 and SHARPIN associate with integrins in membrane ruffles-but outside of adhesion sites-thereby perhaps facilitating integrin transport around the cell surface, while preventing unwanted adhesions forming (Rantala et al 2011;Fournier et al 2002). In osteoblasts, loss of ICAP1 has been found to impair maturation of fibrillar adhesions and to result in reduced fibronection deposition (Brunner et al 2011). Together, the combination of positive and negative regulators of integrin structural and signalling functions enables integrins to control many cell phenotypes, including adhesion and migration.…”

CCM1 and the second life of proteins in adhesion complexes

“…10,75 This subsequently inhibits proper formation of focal adhesions. ICAP1α acts as a negative regulator of integrin function by competing with kindlin for binding to the β1-intergrin tail.…”

“…[69][70][71] ICAP1 binds to the cytoplasmic domain of integrin β1, and thereby, prevents binding of talin [72][73][74] and kindlin. 10,75 Binding of talin and kindlin to integrin β1 is essential for proper integrin-mediated cell adhesion and formation of focal adhesions; 76 hence, inhibition of this binding disrupts proper cell adhesion. Binding of ICAP1 to β1-integrins is mutually exclusive with its binding to CCM1.…”