IQGAP

IQGAPs

Page updated 1st March '04

Despite the name IQGAPs do not have GTPase activating activity, they were so named as when first discovered a homology to the GTPase-activating proteins (GAPs) was recognised (Weissbach et al, 1994). IQGAPs are a conserved group of Rho family (GTPase binding proteins) binding proteins typically present as multiple isoforms that have been implicated in cytokinesis (Kuroda et al, 1996; Brill et al, 1994; Hart et al, 1996; Adachi et al, 1998; Faix et al, 2001).

Figure 1. The structure of the IQGAP family. The CH domain binds F-actin, the function of the six IR (or IQGAP repeats) is presently unknown. The WW domain probably binds a poly-proline type target. The IQ domain binds Ca²⁺/Calmodulin. GRD is the G-protein binding domain and the last domain, the Ras GAP has an unknown function.

The actin-binding properties of IQGAP is presumed to result from the CH or (calponin homology) domain at the N-terminal and the actin binding site has been localised to between 1 and 522 that spans the CH domains and most of the IRs (Mateer et al, 2002). The whole molecule forms a homodimer that bundles actin filaments into an unusual open gel of bundles (Bashour et al, 1997), reminiscent of the gel of bundles formed by alpha-actinin in the presence of ADF/cofilin (Maciver et al, 1991).

Protein	Function	References
actin	A major component of the cytoskeleton	Bashour et al, 1997; Erickson et al, 1997
calmodulin	A calcium binding protein involved in many signalling pathways	Brill et al, 1996; Hart et al, 1996
Cdc42	A monomeric G-protein involved in signalling especially to the actin cytoskeleton	Hart et al, 1996; Erickson et al, 1997
b-catenin	A component of cell adhesions and a signalling molecule of the Wnt pathway.	Briggs et al, 1996; Fukata et al, 1999; Kuroda et al, 1999
E-cadherin		Kuroda et al, 1999
myosin II Essential Light Chain	A regulator of actin/myosin II contractility	Weissbach et al, 1998
Rac1	Another monomeric G-protein involved in signalling especially to the actin cytoskeleton	Bashour et al, 1997.


Table 1 Binding partners of IQGAP1

Surprisingly, Mice in which the IQGAP1 gene has been deleted are normal except that gastric hyperplasia is seen (Li et al, 2000). This might be partly due to the presence of IQGAP2 but the expression of the two does not overlap extensively and so other proteins may be take over.

References:-

Adachi, H., Y. Takahashi, et al. (1997). "Dictyostelium IQGAP-related protein specifically involved in the completion of cytokinesis." J.Cell Biol. 137(4), 891-898.

Bashour, A. M., Fullerton, A. T., Hart, M. J. & Bloom, G. S. (1997) IQGAP1, a Rac- and Cdc42-binding protein, directly binds and cross-links microfilaments., J Cell Biol. 137, 1555-1566.

Briggs, M. W., Li, B. & Sacks, D. B. (2002) IQGAP1-mediated stimulation of transcriptional co-activation by b-catenin is modulated by calmodulin. J.Biol.Chem. 277, 7453-7465.

Briggs, M. W. & Sacks, D. B. (2003) IQGAP proteins are integral components of cytoskeletal regulation. EMBO reports. 4, 571-574.

Brill, S., Li, S., Lyman, C. W., Church, D. M., Wasmuth, J. J., Weissbach, L., Bernards, A. & Snijders, A. J. (1996) The ras GTPase-activating-protein-related human protein IQGAP2 harbors a potential actin binding domain and interacts with calmodulin and Rho family GTPases. Mol Biol Cell. 16, 4869-4878.

Erickson, S.J., Zhang, C., Kahn, R.A., Evans, T. & Cerione, R.A. (1998). J.Biol.Chem. 271, 26850-26854.

Erickson, J. W., Cerione, R. A. & Hart, M. J. (1997) Identification of an actin cytoskeletal complex that includes IQGAP and the Cdc42 GTPase., J.Biol.Chem. 272, 24443-24447.

Faix, J., C. Clougherty, et al. (1998). The IQGAP-related protein DGAP1 interacts with Rac and is involved in the modulation of the F-actin cytoskeleton and control of cell motility. J.Cell Sci. 111, 3059-3071.

Faix, J., Weber, I., Mintert, U., Kohler, J., Lottspeich, F. & Marriott, G. (2001) Recruitment of cortexillin into the cleavage furrow is controlled by rac1 and IQGAP-related proteins. EMBO J. 20, 3705-3715.

Fukata, M., Kuroda, S., Fujii, K., Nakagawa, M., Kawajiri, A., Itoh, N., Shoji, I., Matsuura, Y., Yonehara, S., Fujisawa, H., Kikuchi, A. & Kaibuchi, K. (1999) Cdc42 and Rac1 regulate the interaction of IQGAP1 with b-catenin. J.Biol.Chem. 274, 26044-26050.

Fukata, M., S. Kuroda, et al. (1997). "Regulation of cross-linking of actin filament by IQGAP1, a target for Cdc42." J.Biol.Chem. 272, 29579-29583.

Hart, M. J., Callow, M. C., Souza, B. & Polakis, P. (1996) IQGAP1, a calmodulin-binding protein with a rasGAP-related domain, is a potential effector for cdc42Hs. EMBO J. 15, 2997-3005.

Kuroda, S., Fukata, M., Nakagawa, M. & Kaibuchi, K. (1999) Cdc42, Rac1, and their effector IQGAP1 as molecular switches for cadherin-mediated cell-cell adhesion. BBRC. 262, 1-6.

Li, R., B. Debreceni, et al. (1999). "Localization of the PAK1-, WASP-, and IQGAP1-specific regions of Cdc42." J.Biol.Chem. 274(42), 29648-29654.

Li, S., Wang, Q., Chakladar, A., Bronson, R. T. & Bernards, A. (2000) Gastric hyperplasia in mice lacking the putative Cdc42 effector IQGAP. Mol.Cell Biol. 20, 697-701.

Lippincott, J. and R. Li (1998). "Sequential assembly of myosin II, an IQGAP-like protein, and filamentous actin to a ring structure involved in budding yeast cytokinesis." J.Cell Biol. 140, 355-366.

Maciver, S. K., Wachsstock, D. H., Schwarz, S. H. & Pollard, T. D. (1991b) The actin filament severing protein actophorin promotes the formation of rigid bundles of actin filaments crosslinked with alpha actinin., J. Cell Biol. 115, 1621-1628.

Mateer, S. C., McDaniel, A. E., Nicolas, V., Habermacher, G. M., Lin, M.-J. S., Cromer, D. A., King, M. E. & Bloom, G. S. (2002) The mechanism for regulation of the F-actin bnding activity of IQGAP1 by calcium/calmodulin. J.Biol.Chem. 277, 12324-12333.

McCallum, S. J., Wu, W.J & Cerione, R.A. (1996). "" J.Biol.Chem. 271, 21732-21737.

McCallum, S. J., Erickson, J.W. & Cerione, R.A. (1998). “Characterization of the association of the actin-binding protein, IQGAP, and activated Cdc42 with Golgi membranes.” J.Biol.Chem. 273(35), 22537-22544.

Noritake, J., Fukata, M., Sato, K., Nakagawa, M., Watanabe, T., Izumi, N., Wang, S., Fukata, Y. & Kaibuchi, K. (2004) Positive Role of IQGAP1, an Effector of Rac1, in Actin-Meshwork Formation at Sites of Cell-Cell Contact. Mol. Biol. Cell. 15, 1065-1076.

Weissbach, L., Bernards, A. & Herion, D. W. (1998) Binding of myosin essential light chain complex that includes IQGAP and the Cdc42 GTPase., BBRC. 251, 269-276.