Iqgap1

IQGAP1 is a large, widely expressed protein that regulates many signalling pathways and cellular functions (reviewed in Briggs and Sacks 2003a; Brown and Sacks 2006). With several domains, IQGAP1 is able to bind to a broad spectrum of proteins (Brown and Sacks 2006), thereby modulating actin dynamics, microtubule dynamics, cell-cell adhesion and transcriptional regulation. Recent studies have provided strong evidence that IQGAP1 is a scaffold for the MAPK cascade. IQGAP1 binds directly to MEK1, MEK2, ERK1 and ERK2 (Fig. 5) and regulates their activation in response to EGF (Roy et al. 2004, 2005) and CD44 (Bourguignon et al. 2005). Analogous to KSR, both an increase and a decrease in the IQGAP1 expression level attenuates EGF-dependant activation of MEK and ERK, suggesting that the correct stoichiometry of IQGAP1 to MAPK components is required for efficient propagation of the cascade (Roy et al. 2004, 2005). Interestingly, while ERK associates constitutively with IQGAP1 and the binding is not sensitive to EGF, the interaction between IQGAP1 and MEK1 increases, while that with MEK2 decreases following EGF treatment (Roy et al. 2005). This raises the possibility that IQGAP1 preferentially activates the MEK1 signalling pathway. It has been suggested that MEK1 promotes proliferation, while MEK2 promotes differentiation (Ussar and Voss 2004), and IQGAP1 may therefore regulate the cellular response to MAPK signalling. In addition, new findings reveal that IQGAP1 binds directly to B-Raf and modulates B-Raf kinase activity (Ren et al. 2007). Importantly, deletion of IQGAP1 renders B-Raf insensitive to EGF stimulation. Together these findings highlight the importance of IQGAP1 in the B-Raf/MEK/ ERK signalling cascade.

Following stimulation with growth factors, the MAPK pathway regulates many cellular responses, one of which is the modulation of the cytoskeleton (Reszka et al. 1997). IQGAP1 is a well-documented regulator of the actin and microtubule cytoskeletons (Briggs and Sacks 2003b; Noritake et al. 2005), and it is tempting to speculate that IQGAP1 links MAPK signalling to cytoskeletal dynamics. In support of this idea, both IQGAP1 and ERK2 localise to microtu-bule-associated protein-2 in neuronal cells (Morishima-Kawashima and Kosik 1996; Li et al. 2005).

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