Abstract
Cell adhesion and migration depend on engagement of extracellular matrix ligands by integrins. Integrin activation is dynamically regulated by interactions of various cytoplasmic proteins, such as filamin and integrin activators, talin and kindlin, with the cytoplasmic tail of the integrin β subunit. Although filamin has been suggested to be an inhibitor of integrin activation, direct functional evidence for the inhibitory role of filamin is limited. Migfilin, a filamin-binding protein enriched at cell-cell and cell-extracellular matrix contact sites, can displace filamin from β1 and β3 integrins and promote integrin activation. However, its role in activation and functions of different β integrins in human vascular cells is unknown. In this study, using flow cytometry, we demonstrate that filamin inhibits β1 and αIIbβ3 integrin activation, and migfilin can overcome its inhibitory effect. Migfilin protein is widely expressed in different adherent and circulating blood cells and can regulate integrin activation in naturally-occurring vascular cells, endothelial cells and neutrophils. Migfilin can activate β1, β2 and β3 integrins and promote integrin mediated responses while migfilin depletion impairs the spreading and migration of endothelial cells. Thus, filamin can act broadly as an inhibitor and migfilin is a promoter of integrin activation.
Highlights
During homeostatic processes, such as hemostasis, angiogenesis and inflammation, cells must respond with immediacy and precision to different physiological and pathological cues
We focused on Human umbilical vein endothelial cells (HUVECs) as a high migfilin expresser and a cell where adhesion and migration responses are functionally important and on neutrophil-related cells, where migfilin is expressed at lower levels but where integrin activation is integral to their biological responses
Regulation of integrin activation influences many cellular processes including adhesion, spreading and migration that occur in response to different physiological and pathological agonists
Summary
During homeostatic processes, such as hemostasis, angiogenesis and inflammation, cells must respond with immediacy and precision to different physiological and pathological cues. Integrin heterodimeric adhesion receptors play important roles in this bidirectional communication between cells and their environment by engaging extracellular ligands via their extracellular regions and interacting with different cytoskeletal proteins via their cytoplasmic tails (CTs). The ability of integrins to transit between high and low affinity states for extracellular ligands, inside-out signaling, provides a means to dynamically regulate cellular responses. Such regulation of integrin activation is initiated by their interactions with different intracellular adaptor proteins. Talin and FLN binding sites in integrin b CT overlap and competition between these two proteins may play a significant role in regulating the activation states of integrins [1] and inhibiting talin mediated outside-in signaling [8]. Direct evidence that FLN influences integrin activation (inside-out signaling) directly remains limited
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
