Abstract
Junctional adhesion molecule-A (JAM-A) is a cell-surface glycoprotein that localizes to intercellular junctions and associates with intracellular proteins via PSD95-Dlg-ZO1-binding residues. To define the functional consequences of JAM-A expression, we have produced endothelial cells from JAM-A-deficient mice. We report here that the absence of JAM-A enhanced spontaneous and random motility. In turn, the enhanced motility of JAM-A-negative cells was abrogated either on transfection of exogenous JAM-A or on treatment with inhibitors of glycogen synthase kinase-3beta (GSK-3beta). In addition, in JAM-A-positive cells, motility was enhanced on inactivation of protein kinase Czeta (PKCzeta), which is an inhibitor of GSK-3beta. Although these findings suggested that JAM-A might inhibit GSK-3beta, we found that expression per se of JAM-A did not change the levels of inactive GSK-3beta. Thus, JAM-A expression may regulate effectors of motility that are also downstream of the PKCzeta/GSK-3beta axis. In support of this view, we found that JAM-A absence increased the number of actin-containing protrusions, reduced the stability of microtubules and impaired the formation of focal adhesions. Notably, all the functional consequences of JAM-A absence were reversed either on treatment with GSK-3beta inhibitors or on transfection of full-length JAM-A, but not on transfection of a JAM-A deletion mutant devoid of the PSD95-Dlg-ZO1-binding residues. Thus, by regulating cytoskeletal and adhesive structures, JAM-A expression prevents cell motility, probably in a PSD95-Dlg-ZO1-dependent manner.
Highlights
Junctional adhesion molecule-A (JAM-A), which is known as JAM, JAM-1 and F11R, belongs to a family of cell adhesion molecules that contain two immunoglobulin-like folds in the extracellular domain (Bazzoni, 2003)
A expression may regulate effectors of motility that are downstream of the protein kinase Cζ (PKCζ)/glycogen synthase kinase-3β (GSK-3β) axis. In support of this view, we found that JAM-A absence increased the number of actin-containing protrusions, reduced the stability of microtubules and impaired the formation of focal adhesions
JAM-A localizes to intercellular junctions (Martin-Padura et al, 1998) and mediates processes as diverse as junction assembly (Liu et al, 2000; Liang et al, 2000), leukocyte transmigration (Martin-Padura et al, 1998; Del Maschio et al, 1999), platelet activation (Sobocka et al, 2000) and pathogen infection (Barton et al, 2001; Amieva et al, 2003)
Summary
Junctional adhesion molecule-A (JAM-A), which is known as JAM, JAM-1 and F11R, belongs to a family of cell adhesion molecules that contain two immunoglobulin-like folds in the extracellular domain (Bazzoni, 2003). JAM-A associates directly with at least five different PDZ proteins, namely ZO1 (Bazzoni et al, 2000b; Ebnet et al, 2000), AF6/Afadin (Ebnet et al, 2000), CASK/Lin-2 (Martinez-Estrada et al, 2001), Par3/ASIP (Ebnet et al, 2001; Itoh et al, 2001) and MUPP-1 (Hamazaki et al, 2002), as evaluated by in vitro binding assays. All these interactions are abolished on deletion of the FLVCOOH motif
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