IQGAP1 signaling review

IQGAP1: IQ-motif containing GTPase-activating-like protein-1 review

IQ motif-containing GTPase-activating-like protein-1 (IQGAP1) is a 190 KDa protein that belongs to a conserved family of scaffolds and was first identified in 1994 (Weissbach et al. 1994). The IQGAP family are comprised of three isoforms IQGAP1, IQGAP2 and IQGAP3 in mammals.

IQGAP expression

IQGAP homologs are found in a variety of organisms and the mammalian IQGAPs share 20% amino acid identity with Iqg1p in Saccharomyces cerevisiae (Abel et al. 2015). In humans, IQGAP1 is expressed ubiquitously in tissues while IQGAP2 is expressed mainly in the liver and IQGAP3 is identified in the brain, lung, testis and colon (White et al. 2009).

Cell regulation

IQGAP1 is a regulator of different biological processes including cytoskeleton regulation, cell to cell adhesion, cell migration and cell proliferation (Johnson et al. 2009). The different biological functions regulated by IQGAP1 are mediated by different protein-protein interactions with IQGAP1 that activate cell signalling pathways. IQGAP1 is currently known to bind to about 90 binding partners (White et al. 2012).

IQGAP domains

IQGAP1 interacts with these proteins via its protein domains which include calponin-homology domain (CHD), a tryptophan repeat motif (WW), coil homodimerisation domains, four isoleucine-glutamine domains (IQ) and Ras-GAP-related domain (GRD) and their known interactors (Abel et al. 2015). The CHD domain facilitates binding to filamentous actin (F-actin) and allows the recruitment of F-actin recruitment (Mateer et al. 2002). The WW motif is crucial in allowing ERK 1/2 to bind to IQGAP1, which enhances tumour progression (Jameson et al. 2013).

MAPK pathway regulation

Interestingly, the IQ domain mediates binding to MEK 1/2 or Raf-1, regulating the activity of the MAPK pathway (Roy et al. 2005, Sbroggio et al. 2011). Furthermore, the IQ motif facilitates calmodulin binding, which regulates Ca2+ signalling (Ho et al. 1999). IQGAP1 contains a GTPase-activation-related domain (GRD) but the domain lacks GTPase-activating protein (GAP) activity, resulting in binding partners such as Ras-related C3 botulinum toxin substrate 1 (Rac1) and division cycle 42 (Cdc42) becoming constitutively active because its active GTP cannot be hydrolysed (Hart et al. 1996, Zhang et al. 1997). The GRD lacks enzymatic activity but ultimately facilitates the interactions of Cdc42 and Rac1 binding to IQGAP1.

IQGAP regulates proliferation

The expression of the C-terminus of IQGAP1 which includes the GRD domain was demonstrated to increase the rate of proliferation through a specific Cdc42 pathway (Wang et al. 2009). The Ras GAP C-terminus (RGCT) can bind to ×ý-catenin which may regulate cell-cell adhesion (Fukata et al. 1999). IQGAP1 is frequently overexpressed in a variety of cancers and is located on the chromosome 15q26 (Fukuda et al. 2000).

IQGAP1 & cancer

IQGAP1 has no known mutations so its main mechanism in cancer is the amplification of the gene (Sugimoto et al. 2001). IQGAP1 was identified as being overexpressed in lung, endometrial, ovarian, gastric, colon, and breast cancer, as well as hepatocellular carcinoma (HCC) and melanoma (Johnson et al. 2009). In gastric cancer and HCC, IQGAP1 increased in protein and mRNA levels while IQGAP2 mRNA levels were down regulated (Morris et al. 2005, Xia et al. 2014). This may demonstrate that IQGAP1 acts as an oncogene, and IQGAP2 as a possible tumour suppressor.

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