Article

Tyrosine Phosphorylation of Integrin 3 Regulates Kindlin-2 Binding and Integrin Activation

Department of Molecular Cardiology, Joseph J Jacobs Center for Thrombosis and Vascular Biology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2010; 285(40):30370-4. DOI: 10.1074/jbc.C110.134247
Source: PubMed

ABSTRACT Kindlins are essential for integrin activation in cell systems and do so by working in a cooperative fashion with talin via their direct interaction with integrin β cytoplasmic tails (CTs). Kindlins interact with the membrane-distal NxxY motif, which is distinct from the talin-binding site within the membrane-proximal NxxY motif. The Tyr residues in both motifs can be phosphorylated, and it has been suggested that this modification of the membrane-proximal NxxY motif negatively regulates interaction with the talin head domain. However, the influence of Tyr phosphorylation of the membrane-distal NxxY motif on kindlin binding is unknown. Using mutational analyses and phosphorylated peptides, we show that phosphorylation of the membrane-distal NITY(759) motif in the β(3) CT disrupts kindlin-2 recognition. Phosphorylation of this membrane-distal Tyr also disables the ability of kindlin-2 to coactivate the integrin. In direct binding studies, peptides corresponding to the non-phosphorylated β(3) CT interacted well with kindlin-2, whereas the Tyr(759)-phosphorylated peptide failed to bind kindlin-2 with measurable affinity. These observations indicate that transitions between the phosphorylated and non-phosphorylated states of the integrin β(3) CT determine reactivity with kindlin-2 and govern the role of kindlin-2 in regulating integrin activation.

0 Followers
 · 
163 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: With the increasing operating voltages of power systems, the reliability of insulating systems which depends on the defects within the insulation becomes more and more important. It is necessary to develop an accurate, simple and reliable method for defect detection. In this paper, an acoustic signal analysis method for detection of defects in insulation systems based on wavelet transforms is introduced. Some applications of wavelet transforms in detection of defects in insulating systems are given
    Electrical Insulating Materials, 1995. International Symposium on; 10/1995
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Integrins are essential adhesion receptors found on the surfaces of all metazoan cells. As regulators of cell migration and extracellular matrix assembly, these membrane-spanning heterodimers are critical for embryonic development, tissue repair and immune responses. Signals transmitted by integrins from outside to inside the cell promote cell survival and proliferation, but integrin affinity for extracellular ligands can also be controlled by intracellular cues. This bidirectional signaling is mediated by the short cytoplasmic tails of the two integrin subunits. Recent structural and functional studies of various integrin fragments and complexes between the cytoplasmic tails and intracellular proteins, such as talin, have provided new insight into the signaling processes centered around the tails, particularly inside-out integrin activation.
    Trends in Biochemical Sciences 04/2011; 36(4):191-8. DOI:10.1016/j.tibs.2010.11.002 · 13.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Signal transduction across biological membranes is central to life. This process generally happens through communication between different domains and hierarchical coupling of information. Here, we review structural and thermodynamic principles behind transmembrane (TM) signal transduction and discuss common themes. Communication between signaling domains can be understood in terms of thermodynamic and kinetic principles, and complex signaling patterns can arise from simple wiring of thermodynamically coupled domains. We relate this to functions of several signal transduction systems: the M2 proton channel from influenza A virus, potassium channels, integrin receptors, and bacterial kinases. We also discuss key features in the structural rearrangements responsible for signal transduction in these systems.
    Annual review of biochemistry 06/2011; 80:211-37. DOI:10.1146/annurev-biochem-091008-152423 · 26.53 Impact Factor
Show more