Identification and Functional Studies of a New Nrf2 Partner IQGAP1: A Critical Role in the Stability and Transactivation of Nrf2

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Background: IQGAP1 is a scaffold protein that modulates diverse signaling pathways. Results: IQGAP1 binds to estrogen receptor-␣ (ER␣) and ER␤, and knockdown of IQGAP1 impairs 17␤-estradiol (E 2 )-stimulated transcriptional activation in human breast epithelial cells. Conclusion: IQGAP1 modulates ER␣ function and is required for maximal E 2 function. Significance: IQGAP1 might be a therapeutic target for patients with breast carcinoma.

Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 84%

IQGAP1 Binds to Estrogen Receptor-α and Modulates Its Function

Erdemir¹,

Sacks

2014

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“…Some nuclear functions of IQGAP1 are elicited via direct interaction with and regulation of transcription factors, such as estrogen receptor ␣ (ER␣) and nuclear factor erythroid-related factor 2 (19,20). In addition, IQGAP1 binds to ␤-catenin and enhances its nuclear accumulation and transcriptional co-activation (21).…”

mentioning

confidence: 99%

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

Sayedyahossein

Hedman

et al. 2016

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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...

“…We have recently identified IQGAP1 (IQ motif-containing GTPase-activating protein 1) as a novel binding partner of Nrf2 (14). Like other IQGAP family proteins such as IQGAP2 and IQGAP3, IQGAP1 shares conserved protein structure, including calmodulin-binding IQ motifs and the GTPase-activating protein homology domain (15).…”

mentioning

confidence: 99%

The Ras GTPase-activating-like Protein IQGAP1 Mediates Nrf2 Protein Activation via the Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase (ERK) Kinase (MEK)-ERK Pathway

Cheung

Lee

Shu

et al. 2013

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