Premium
Small GTPases and LFA‐1 reciprocally modulate adhesion and signaling
Author(s) -
Mor Adam,
Dustin Michael L.,
Philips Mark R.
Publication year - 2007
Publication title -
immunological reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.839
H-Index - 223
eISSN - 1600-065X
pISSN - 0105-2896
DOI - 10.1111/j.1600-065x.2007.00538.x
Subject(s) - rap1 , microbiology and biotechnology , biology , guanine nucleotide exchange factor , ectodomain , gtpase , cell adhesion , signal transduction , integrin , cell adhesion molecule , receptor , biochemistry , cell
Summary: 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.