Small GTPases and LFA-1 reciprocally modulate adhesion and signaling.
Leukocyte-function-associated antigen-1 (LFA-1) is an integrin that is critical for T-cell adhesion and immunologic responses. As a transmembrane receptor and adhesion molecule, LFA-1 signals bidirectionally, whereby information about extracellular ligands is passed outside-in while cellular activation is transmitted inside-out to the adhesive ectodomain. Here, we review the role of small guanosine triphosphatases (GTPases) in LFA-1 signaling. Rap1, a Ras-related GTPase, appears to be central to LFA-1 function. Rap1 is regulated by receptor signaling [e.g. T-cell receptor (TCR), CD28, and cytotoxic T-lymphocyte antigen-4 (CTLA-4)] and by adapter proteins [e.g. adhesion and degranulation-promoting adapter protein (ADAP) and Src kinase-associated phosphoprotein of 55 kDa (SKAP-55)]. Inside-out signaling flows through Rap1 to regulator of adhesion and cell polarization enriched in lymphoid tissues (RAPL) and Rap1-GTP interacting adapter molecule (RIAM) that act in conjunction with the cytoskeleton on the cytosolic domain of LFA-1 to increase adhesion of the ectodomain. Outside-in signaling also relies on small GTPases such as Rho proteins. Vav-1, a guanine nucleotide exchange factor for Rho proteins, is activated as a consequence of LFA-1 engagement. Jun-activating binding protein-1 (JAB-1) and cytohesin-1 have been implicated as possible outside-in signaling intermediates. We have recently shown that Ras is also downstream of LFA-1 engagement: LFA-1 signaling through phospholipase D (PLD) to RasGRP1 was required for Ras activation on the plasma membrane following stimulation of TCR.
Mor
Adam
A
Department of Medicine, NYU School of Medicine, New York, NY 10016, USA.
Dustin
Michael L
ML
Philips
Mark R
MR
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology* / Q000378:metabolism*; D018448:Models, Immunological; D020559:Monomeric GTP-Binding Proteins / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D016169:Lymphocyte Function-Associated Antigen-1; D020559:Monomeric GTP-Binding Proteins