Adhesion molecules are known to play an important role in endothelial activation and angiogenesis. Here we determined the functional role of IQGAP1 in the regulation of endothelial adherens junctions. VE-cadherin is found to be associated with actin filaments and thus stable, but IQGAP1 at intercellular junctions is not bound to actin filaments and thus labile. Expression of GFP labeled VE-α-catenin is shown to increase the electrical resistance across HUVEC monolayers and diminishes endogenous labile IQGAP1 at the intercellular junctions. Knockdown of endogenous IQGAP1 enhances intercellular adhesion in HUVECs by increasing the association of VE-cadherin with P120 and β-catenin. IQGAP1 knockdown also decreases the interaction of N-cadherin with P120 and β-catenin. Together, these results suggest that a labile pool of IQGAP1 at intercellular junctions disassembles adherens junctions and thus impairs endothelial cell-cell adhesion.
Urao, N.; Razvi, M.; Oshikawa, J.; McKinney, R.D.; Chavda, R.; Bahou, W.F.; Fukai, T.; Ushio-Fukai, M. IQGAP1 is involved in post-ischemic neovascularization by regulating angiogenesis and macrophage infiltration. PLoS One 2010, 5, e13440.
Corada, M.; Mariotti, M.; Thurston, G.; Smith, K.; Kunkel, R.; Brockhaus, M.; Lampugnani, M.G.; Martin-Padura, I.; Stoppacciaro, A.; Ruco, L.; et al. Vascular endothelial-cadherin is an important determinant of microvascular integrity in vivo. Proc. Natl. Acad. Sci. USA 1999, 96, 9815–9820.
Wu, Y.; Vendome, J.; Shapiro, L.; Ben-Shaul, A.; Honig, B. Transforming binding affinities from three dimensions to two with application to cadherin clustering. Nature 2011, 475, 510–513.
Ohkubo, T.; Ozawa, M. p120(ctn) binds to the membrane-proximal region of the E-cadherin cytoplasmic domain and is involved in modulation of adhesion activity. J. Biol. Chem 1999, 274, 21409–21415.
Kuroda, S.; Fukata, M.; Nakagawa, M.; Fujii, K.; Nakamura, T.; Ookubo, T.; Izawa, I.; Nagase, T.; Nomura, N.; Tani, H.; et al. Role of IQGAP1, a target of the small GTPases Cdc42 and Rac1, in regulation of E-cadherin- mediated cell-cell adhesion. Science 1998, 281, 832–835.
Kuroda, S.; Fukata, M.; Nakagawa, M.; Kaibuchi, K. Cdc42, Rac1, and their effector IQGAP1 as molecular switches for cadherin-mediated cell-cell adhesion. Biochem. Biophys. Res. Commun 1999, 262, 1–6.
Mateer, S.C.; Morris, L.E.; Cromer, D.A.; Bense？or, L.B.; Bloom, G.S. Actin filament binding by a monomeric IQGAP1 fragment with a single calponin homology domain. Cell Motil. Cytoskeleton 2004, 58, 231–241.
Fey, E.G.; Wan, K.M.; Penman, S. Epithelial cytoskeletal framework and nuclear matrix-intermediate filament scaffold: Three-dimensional organization and protein composition. J. Cell. Biol 1984, 98, 1973–1984.
Kuroda, S.; Fukata, M.; Kobayashi, K.; Nakafuku, M.; Nomura, N.; Iwamatsu, A.; Kaibuchi, K. Identification of IQGAP as a putative target for the small GTPases, Cdc42 and Rac1. J. Biol. Chem 1996, 271, 23363–23367.
Weissbach, L.; Settleman, J.; Kalady, M.F.; Snijders, A.J.; Murthy, A.E.; Yan, Y.X.; Bernards, A. Identification of a human rasGAP-related protein containing calmodulin-binding motifs. J. Biol. Chem 1994, 269, 20517–20521.
Fukata, M.; Nakagawa, M.; Itoh, N.; Kawajiri, A.; Yamaga, M.; Kuroda, S.; Kaibuchi, K. Involvement of IQGAP1, an effector of Rac1 and Cdc42 GTPases, in cell-cell dissociation during cell scattering. Mol. Cell. Biol 2001, 21, 2165–2183.
Wegener, J.; Keese, C.R.; Giaever, I. Electric cell-substrate impedance sensing (ECIS) as a noninvasive means to monitor the kinetics of cell spreading to artificial surfaces. Exp. Cell Res 2000, 259, 158–166.
