IQGAPs as Key Regulators of Actin-cytoskeleton Dynamics

Watanabe, Takashi; Wang, Shujie; Kaibuchi, Kozo

doi:10.1247/csf.15003

Cited by 69 publications

(71 citation statements)

References 63 publications

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“…Like ISG15 knockdown, UbCH8 depletion reversed cytoskeletal and morphological alterations. In agreement with previous studies (Zhao et al, 2005), the scaffolding protein IQGAP1 (Watanabe et al, 2015) was confirmed as an (Watanabe et al, 2015).…”

Section: Discussionsupporting

confidence: 92%

Coping with Loss: Cell Adaptation to Cytoskeleton Disruption

McGarry

Olson

2016

Developmental Cell

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Section: Discussionsupporting

confidence: 92%

Coping with Loss: Cell Adaptation to Cytoskeleton Disruption

McGarry

Olson

2016

Developmental Cell

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“…1A). These regions serve as platforms for selective interactions with structurally and functionally diverse effectors, such as p21-activated kinase 1 (PAK1), p67phox, a member of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family as well as IQ motifcontaining GTPase-activating proteins (IQGAPs) (21,22).…”

mentioning

confidence: 99%

Unraveling the molecular mechanism of interactions of the Rho GTPases Cdc42 and Rac1 with the scaffolding protein IQGAP2

Ozdemir

Jang

Gürsoy

et al. 2018

Journal of Biological Chemistry

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IQ motif-containing GTPase-activating protein (IQGAP) scaffolding proteins play central roles in cell-cell adhesion, polarity, and motility. The Rho GTPases Cdc42 and Rac1, in their GTPbound active forms, interact with all three human IQGAPs. The IQGAP-Cdc42 interaction promotes metastasis by enhancing actin polymerization. However, despite their high sequence identity, Cdc42 and Rac1 differ in their interactions with IQGAP. Two Cdc42 molecules can bind to the Exdomain and the RasGAP site of the GTPaseactivating protein (GAP)-related domain (GRD) of IQGAP and promote IQGAP dimerization. Only one Rac1 molecule might bind to the RasGAP site of GRD and may not facilitate the dimerization, and the exact mechanism of Cdc42 and Rac1 binding to IQGAP is unclear. Using all-atom molecular dynamics simulations, site-directed mutagenesis, and Western blotting, we unraveled the detailed mechanisms of Cdc42 and Rac1 interactions with IQGAP2. We observed that Cdc42 binding to the Ex-domain of GRD of IQGAP2 (GRD2) releases the Ex-domain at the C-terminal region of GRD2, facilitating IQGAP2 dimerization. Cdc42 binding to the Ex-domain promoted allosteric changes in the RasGAP site, providing a binding site for the second Cdc42 in the RasGAP site. Of note, the Cdc42 "insert loop" was important for the interaction of the first Cdc42 with the Ex-domain. By contrast, differences in Rac1 insert loop sequence and structure precluded its interaction with the Ex-domain. Rac1 could bind only to the RasGAP site of apo-GRD2 and could not facilitate IQGAP2 dimerization. Our detailed mechanistic insights help decipher how Cdc42 can stimulate actin polymerization in metastasis.The Rho GTPase family is a subfamily of the Ras GTPase superfamily. Rho GTPases regulate multiple cellular processes such as growth, survival, cell invasion, cell motility and vesicle trafficking by interacting with effector molecules (1-4). To date, the mammalian Rho GTPase family includes 22 members; Cdc42, Rac1, and RhoA are the most studied among them (5).Rho GTPases are distinguished from other GTPases by the presence of an "insert loop" which is rich in charged residues in an α-helical motif (Fig. http://www.jbc.org/cgi

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“…Three IQGAP family members (named IQGAP1, IQGAP2, and IQGAP3) have been identified in mammals (10). The expression of IQGAP2 is restricted to liver (11), and IQGAP3 is reported to be expressed in lung, brain, testis, small intestine, and colon (12).…”

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confidence: 99%

IQGAP1 Binds to Yes-associated Protein (YAP) and Modulates Its Transcriptional Activity

Sayedyahossein

Hedman

et al. 2016

Journal of Biological Chemistry

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During development, the Hippo signaling pathway regulates key physiological processes, such as control of organ size, regeneration, and stem cell biology. Yes-associated protein (YAP) is a major transcriptional co-activator of the Hippo pathway. The scaffold protein IQGAP1 interacts with more than 100 binding partners to integrate diverse signaling pathways. In this study, we report that IQGAP1 binds to YAP and modulates its activity. The Hippo signaling pathway comprises numerous proteins that regulate organ size and shape, regeneration, and stem cell biology (1). The Hippo pathway responds to several stimuli, such as stress, polarity, and adhesion cues and has been implicated in tumorigenesis (2). The primary components of this cascade are a kinase module and a transcriptional module. The transcriptional module consists of yes-associated protein (YAP) 2 and the transcriptional co-activator with PDZ-binding motif (TAZ), which together drive the activities downstream of the Hippo pathway (3). Importantly, YAP shuttles between the cytoplasm and nucleus. Nevertheless, nuclear translocation of YAP is not sufficient for induction of transcriptional activity because YAP does not contain a DNA-binding region. Nuclear YAP activity is elicited by binding to transcription factors. Among these, TEA domain family members (TEADs) are the major transcription factors driving YAP-mediated gene transcription (4, 5). YAP activity is regulated through phosphorylation-dependent and -independent mechanisms. When Hippo is ON, YAP gets phosphorylated, and its co-transcriptional activity is inhibited. The kinase module of the Hippo pathway, including large tumor suppressor 1 and 2 (LATS1/2) and mammalian STE20-like protein kinase 1 and 2 (MST1/2), inhibits YAP by catalyzing phosphorylation at Ser 127 or Ser 381 (6). Phosphorylation of YAP at Ser 127 induces its interaction with 14-3-3, which leads to retention of YAP in the cytoplasm, thereby inhibiting transcriptional activity. Phosphorylation of YAP at Ser 381 (Ser 381 in mice corresponds to residue Ser 397 in humans; all reference to phosphorylation at this site will be described as Ser 381 ) leads to its ubiquitination and cytoplasmic degradation. Furthermore, other regulatory proteins, such as NF2 (neurofibromatin 2) and KIBRA (kidney and brain expressed protein), form a complex to activate the Hippo kinase module, thereby inhibiting YAP nuclear activity (7). YAP can also be modulated by direct protein-protein interactions. For example, the angiomotin (AMOT) family of proteins binds to YAP and promotes its cytoplasmic retention (8). In contrast, direct binding of YAP to multiple ankyrin repeats single KH domain-containing protein (MASK) in the nucleus potentiates YAP-mediated transcriptional activity (9).IQGAPs are evolutionary conserved, scaffold proteins with multiple functions. Three IQGAP family members (named IQGAP1, IQGAP2, and IQGAP3) have been identified in mammals (10). The expression of IQGAP2 is restricted to liver (11), and IQGAP3 is reported to be expressed in lung...

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IQGAPs as Key Regulators of Actin-cytoskeleton Dynamics

Cited by 69 publications

References 63 publications

Coping with Loss: Cell Adaptation to Cytoskeleton Disruption

Coping with Loss: Cell Adaptation to Cytoskeleton Disruption

Unraveling the molecular mechanism of interactions of the Rho GTPases Cdc42 and Rac1 with the scaffolding protein IQGAP2

IQGAP1 Binds to Yes-associated Protein (YAP) and Modulates Its Transcriptional Activity

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