Díaz-González F, Forsyth J, Steiner B, Ginsberg M H
Department of Vascular Biology, Scripps Research Institute, La Jolla, California 92037, USA.
Mol Biol Cell. 1996 Dec;7(12):1939-51. doi: 10.1091/mbc.7.12.1939.
Occupancy of integrin adhesion receptors can alter the functions of other integrins and cause partition of the ligand-occupied integrin into focal adhesions. Ligand binding also changes the conformation of integrin extracellular domains. To explore the relationship between ligand-induced conformational change and integrin signaling, we examined the effect of ligands specific for integrin alpha IIb beta 3 on the functions of target integrins alpha 5 beta 1 and alpha 2 beta 1. We report that binding of integrin-specific ligands to a suppressive integrin can inhibit the function of other target integrins (trans-dominant inhibition). Trans-dominant inhibition is due to a blockade of integrin signaling. Furthermore, this inhibition involves both a conformational change in the extracellular domain and the presence of the beta cytoplasmic tail in the suppressive integrin. Similarly, ligand-induced recruitment of alpha IIb beta 3 to focal adhesions also involves a conformational rearrangement of its extracellular domain. These findings imply that the ligand-induced conformational changes can propagate from an integrin's extracellular to its intracellular face. Trans-dominant inhibition by integrin ligands may coordinate integrin signaling and can lead to unexpected biological effects of integrin-specific inhibitors.
整合素黏附受体的占据可改变其他整合素的功能，并导致配体占据的整合素在黏着斑中分隔。配体结合还会改变整合素细胞外结构域的构象。为了探究配体诱导的构象变化与整合素信号传导之间的关系，我们研究了整合素αIIbβ3特异性配体对靶整合素α5β1和α2β1功能的影响。我们报告，整合素特异性配体与抑制性整合素的结合可抑制其他靶整合素的功能（反式显性抑制）。反式显性抑制是由于整合素信号传导的阻断。此外，这种抑制涉及细胞外结构域的构象变化以及抑制性整合素中β细胞质尾的存在。同样，配体诱导的αIIbβ3募集到黏着斑也涉及其细胞外结构域的构象重排。这些发现表明，配体诱导的构象变化可从整合素的细胞外表面传播到其细胞内表面。整合素配体的反式显性抑制可能协调整合素信号传导，并可能导致整合素特异性抑制剂产生意想不到的生物学效应。
