Article

Kindlin-2 (Mig-2): a co-activator of β3 integrins

Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH 44195, USA.
The Journal of Cell Biology (Impact Factor: 9.69). 06/2008; 181(3):439-46. DOI: 10.1083/jcb.200710196
Source: PubMed

ABSTRACT Integrin activation is essential for dynamically linking the extracellular environment and cytoskeletal/signaling networks. Activation is controlled by integrins' short cytoplasmic tails (CTs). It is widely accepted that the head domain of talin (talin-H) can mediate integrin activation by binding to two sites in integrin beta's CT; in integrin beta(3) this is an NPLY(747) motif and the membrane-proximal region. Here, we show that the C-terminal region of integrin beta(3) CT, composed of a conserved TS(752)T region and NITY(759) motif, supports integrin activation by binding to a cytosolic binding partner, kindlin-2, a widely distributed PTB domain protein. Co-transfection of kindlin-2 with talin-H results in a synergistic enhancement of integrin alpha(IIb)beta(3) activation. Furthermore, siRNA knockdown of endogenous kindlin-2 impairs talin-induced alpha(IIb)beta(3) activation in transfected CHO cells and blunts alpha(v)beta(3)-mediated adhesion and migration of endothelial cells. Our results thus identify kindlin-2 as a novel regulator of integrin activation; it functions as a coactivator.

0 Followers
 · 
100 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The association of aberrant expression of Kindlin-2 with tumor progression has been reported in recent years. The purpose of this study was to investigate the expression of Kindlin-2 in hepatocellular carcinoma (HCC), and to evaluate its clinical and prognostic significance. The mRNA and protein levels of Kindlin-2 in HCC and adjacent non-cancerous tissues were examined by real-time PCR and western blotting. The relationships between Kindlin-2 expression, clinicopathological features and postoperative survival of HCC patients were also evaluated. Kindlin-2 expression was higher in HCC tissues as compared to adjacent non-cancerous tissues at both mRNA and protein levels (P < 0.05, respectively). Positive expression of Kindlin-2 was significantly correlated with larger tumor size (P = 0.034), capsular invasion (P = 0.009), microvascular invasion (P = 0.028) and poor prognosis of HCC patients (P < 0.001). Moreover, multivariate survival analysis identified Kindlin-2 as an independent prognostic factor for overall and disease-free survival of HCC patients (P = 0.018 and 0.001, respectively). Taken together, our findings suggested that Kindlin-2 was highly expressed in HCC tissues and was closely related to clinical progression. Therefore, Kindlin-2 protein could be a potential biomarker for predicting poor prognosis of HCC patients after surgery.
    Pathology - Research and Practice 10/2014; DOI:10.1016/j.prp.2014.09.011 · 1.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion.
    Nature Communications 12/2014; 5:5880. DOI:10.1038/ncomms6880 · 10.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The critical roles of integrins in thrombosis have enabled the successful development and clinical use of the first generation of integrin antagonists as represented by abciximab (Reopro), eptifibatide (Integrilin), and tirofiban (Aggrastat). These integrin αIIbβ3 antagonists are not only potent antithrombotics but also have significant side effects. In particular, their induction of ligand-induced integrin conformational changes is associated with thrombocytopenia. Increased bleeding risk prevents integrin antagonists from being used at higher doses and in patients at risk for bleeding. To address the ligand-induced conformational changes caused by current integrin antagonists, compounds that minimally induce conformational changes in integrin αIIbβ3 have been developed. Recent studies on the mechanisms of integrin signaling suggest that selectively targeting integrin outside-in signaling mechanisms allows for potent inhibition of thrombosis, while maintaining hemostasis in animal models.
    Arteriosclerosis Thrombosis and Vascular Biology 09/2014; DOI:10.1161/ATVBAHA.114.303411 · 5.53 Impact Factor

Preview (3 Sources)

Download
2 Downloads
Available from