De Novo Expression of the Integrin α5β1 Regulates αvβ3-mediated Adhesion and Migration on Fibrinogen

Abstract

Recent evidence demonstrates that interactions between different integrins that are present on the cell surface can strongly influence the adhesive function of individual receptors. In this report, we show that Chinese hamster ovary cells that express the integrin ␣ v ␤ 3 in the absence of ␣ 5 ␤ 1 demonstrate increased adhesion and migration on fibrinogen. Furthermore, ␣ v ␤ 3 -mediated adhesion to fibrinogen is not augmented by the soluble agonist, MnCl 2 , suggesting that ␣ v ␤ 3 exists in a higher affinity state in these cells. De novo expression of wild-type ␣ 5 ␤ 1 negatively regulates ␣ v ␤ 3 -mediated adhesion and migration. This effect is not seen with expression of a chimeric ␣ 5 ␤ 1 integrin in which the cytoplasmic portion of the ␣ 5 integrin subunit is replaced by the cytoplasmic portion of the ␣ 4 integrin. In addition, it does not require ligation of ␣ 5 ␤ 1 by fibronectin. Cells that express a constitutively active ␤ 3 integrin that contains a point mutation in the conserved membrane proximal region of the cytoplasmic tail, D723R, are resistant to the effect of ␣ 5 ␤ 1 expression. These data provide additional evidence of "cross-talk" between the integrins ␣ 5 ␤ 1 and ␣ v ␤ 3 , and support the idea that ␣ 5 ␤ 1 regulates ␣ v ␤ 3 -mediated ligand binding. This provides a relevant biological mechanism whereby variations in ␣ 5 ␤ 1 expression in vivo may modulate activation of ␣ v ␤ 3 to influence its adhesive function.Integrins are transmembrane glycoproteins that are the principle mediators of cell interactions with the extracellular matrix (ECM) 1 (1-3). They are composed of noncovalently associated ␣ and ␤ subunits, which together determine the ligand-binding specificity of the receptor. Integrin-ECM interactions are essential for a diverse variety of important biological processes, including embryogenesis, cell survival, and wound healing (4 -6). During wound healing, alterations in integrin expression coincide with deposition of a newly formed provisional ECM whose primary structural components include fibrinogen (FBG) and fibronectin (FN) (5, 7).Members of the ␤ 3 integrin family are the primary receptors that mediate cell interactions with FBG (8 -10). In platelets, the interaction of ␣ IIb ␤ 3 with FBG is dependent upon agoniststimulated signaling events that alter the ligand-binding function of the ␣ IIb ␤ 3 receptor, a process termed "integrin activation" (11). The adhesive function of ␣ v ␤ 3 also seems to be regulated by intracellular events as recent studies indicate that the basal affinity of this receptor varies both by intracellular location and among cell types (12-14). Activation of ␣ v ␤ 3 results in different functional states of the receptor that influence important integrin-dependent events, including cell migration, angiogenesis, and metastatic activity (14, 15). Although rapid regulation of ␣ v ␤ 3 function may represent a common mechanism for the modulation of cell-ECM interactions, little is known about the molecular events that affect receptor affinity.Recent evidence demo...

Transendothelial migration enhances integrin-dependent human neutrophil chemokinesis

“…7A). A relationship between ␣ 5 ␤ 1 expression and ␣ v ␤ 3 -mediated adhesion and motility on fibrinogen has been confirmed [30]. Together, these results indicate that multi-integrin involvement is necessary for effective and efficient neutrophil motility.…”

Integrin α3β1, a Novel Receptor for α3(IV) Noncollagenous Domain and a Trans-dominant Inhibitor for Integrin αvβ3

“…One possible mechanism is by transdominant inhibition and activation of ␣v␤3 by other integrins. In this context, ␣v␤3 affinity is higher in cells deficient in integrin ␣5␤1 and increased expression of ␣5␤1 reduces ␣v␤3-mediated adhesion and migration (14). Similarly, integrin ␣3␤1 has been demonstrated to alter the function of other integrins and the formation of stress fibers in mouse keratinocytes (15).…”

“…However, as shown above, integrin ␣3␤1 binds to the ␣3NC1 domain in solution. Furthermore, it is well known that the affinity of ␣v integrins can be altered by the transdominant effect of other integrins (14,15). To test whether integrin ␣3␤1 can indeed alter the affinity of ␣v integrins, we measured the activation status of ␣v integrins in B10 and R10 cells.…”

Competition for Talin Results in Trans-dominant Inhibition of Integrin Activation

“…One form of integrin cross-talk occurs when ligation of one integrin inhibits the activation of a second integrin, the socalled trans-dominant inhibition of integrin activation (9). Trans-dominant inhibition mediated by ␤ 1 , ␤ 2 , or ␤ 3 integrins has been demonstrated in a variety of cell types and shown to regulate cell adhesion, spreading, migration, clot retraction, and differentiation (9,10,14,18,20). Trans-dominant integrin inhibition may be relevant physiologically and clinically in a number of settings.…”