Phosphorylation of CLASP2 by GSK-3 beta regulates its interaction with IQGAP1, EB1 and microtubules

Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan.
Journal of Cell Science (Impact Factor: 5.43). 09/2009; 122(Pt 16):2969-79. DOI: 10.1242/jcs.046649
Source: PubMed


Polarised cell migration is required for various cell behaviours and functions. Actin and microtubules are coupled structurally and distributed asymmetrically along the front-rear axis of migrating cells. CLIP-associating proteins (CLASPs) accumulate near the ends of microtubules at the front of migrating cells to control microtubule dynamics and cytoskeletal coupling. Regional inhibition of GSK-3beta is responsible for this asymmetric distribution of CLASPs. However, it is not known how GSK-3beta regulates the activity of CLASPs for linkage between actin and microtubules. Here we identified IQGAP1, an actin-binding protein, as a novel CLASP-binding protein. GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules. At the leading edges of migrating fibroblasts, CLASP2 near microtubule ends partially colocalises with IQGAP1. Expression of active GSK-3beta abrogates the distribution of CLASP2 on microtubules, but not that of a nonphosphorylatable CLASP2 mutant. The phosphorylated CLASP2 does not accumulate near the ends of microtubules at the leading edges. Thus, phosphorylation of CLASP2 by GSK-3beta appears to control the regional linkage of microtubules to actin filaments through IQGAP1 for cell migration.

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Available from: Kozo Kaibuchi, Jul 08, 2015
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    • "perative to note that IQGAP1 functions as a regulator of - catenin - mediated gene transcription ( Fukata et al . , 1999 ; Wang et al . , 2008 ; Briggs et al . , 2002 ) . Direct binding of APC ( Watanabe et al . , 2004 ; Aoki and Taketo , 2007 ) or protein phosphatase 2A ( PP2A ) ( Suzuki et al . , 2005 ) and an indirect interaction with GSK - 3 ( Watanabe et al . , 2009 ) signifies the biological relevance of IQGAP1 in Wnt signaling ( Fig . 7A ) . Most importantly , a region between the IQ domains and the GRD of IQGAP1 binds the C - terminus of Disheveled ( DVL ) ( Goto et al . , 2013b ) and direct binding of - catenin itself to the RGCT domain ( Fukata et al . , 1999 ) confirms a role for IQGAP1 in th"
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    • "GSK-3 can phosphorylate many microtubule binding proteins such as APC, EB proteins, CLIP-associating proteins, Tau, and collapsin response-associated proteins (Akhmanova et al., 2001; Cole et al., 2004; Hur and Zhou, 2010; Zumbrunn et al., 2001). Phosphorylation of these proteins by GSK- 3 inhibits their ability to bind to microtubules, thus destabilizing microtubules (Akhmanova et al., 2001; Watanabe et al., 2009; Zumbrunn et al., 2001). For example, binding of APC to the microtubule is negatively regulated by GSK3-mediated phosphorylation (Zhou et al., 2004; Zumbrunn et al., 2001). "
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    • "These centrosomal MTs are oriented towards the cell cortex and, in particular, towards cadherin-mediated contacts (Shaw et al., 2007; Stehbens et al., 2006). The plus ends of MTs could be at least transiently anchored to adhesion areas through dynein (Ligon and Holzbaur, 2007; Ligon et al., 2001) and MT plus-end tracking proteins, such as CLIP-170 (Stehbens et al., 2006), p150 Glued (also known as DCTN1) (Shaw et al., 2007) or IQGAP1 (Fukata et al., 2002; Watanabe et al., 2009). These MTs would then mediate the delivery of cadherin-containing vesicles to the plasma membrane (Chen et al., 2003; Mary et al., 2002; Teng et al., 2005), or the delivery of other junctional proteins (Shaw et al., 2007). "

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