IQGAP1 Binds to Estrogen Receptor-α and Modulates Its Function

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2014 Feb 20

PMID 24550401

Citations 24

Authors

Huseyin H Erdemir

Zhigang Li

David B Sacks

Affiliations

Soon will be listed here.

Abstract

The estrogen receptor (ER) is a steroid hormone receptor that acts as a transcription factor, modulating genes that regulate a vast range of cellular functions. IQGAP1 interacts with several signaling proteins, cytoskeletal components, and transmembrane receptors, thereby serving as a scaffold to integrate signaling pathways. Both ERα and IQGAP1 contribute to breast cancer. In this study, we report that IQGAP1 binds ERα and ERβ. In vitro analysis with pure proteins revealed a direct interaction between IQGAP1 and ERα. Investigation with multiple short fragments of each protein showed that ERα binds to the IQ domain of IQGAP1, whereas the hinge region of ERα is responsible for binding IQGAP1. In addition, IQGAP1 and ERα co-immunoprecipitated from cells, and the association was modulated by estradiol. The interaction has functional effects. Knockdown of endogenous IQGAP1 attenuated the ability of estradiol to induce transcription of the estrogen-responsive genes pS2, progesterone receptor, and cyclin D1. These data reveal that IQGAP1 binds to ERα and modulates its transcriptional function, suggesting that IQGAP1 might be a target for therapy in patients with breast carcinoma.

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References

Brown A, Jeltsch J, Roberts M, Chambon P . Activation of pS2 gene transcription is a primary response to estrogen in the human breast cancer cell line MCF-7. Proc Natl Acad Sci U S A. 1984; 81(20):6344-8. PMC: 391920. DOI: 10.1073/pnas.81.20.6344. View

Goto T, Sato A, Shimizu M, Adachi S, Satoh K, Iemura S . IQGAP1 functions as a modulator of dishevelled nuclear localization in Wnt signaling. PLoS One. 2013; 8(4):e60865. PMC: 3618174. DOI: 10.1371/journal.pone.0060865. View

Kuroda S, Fukata M, Nakagawa M, Fujii K, Nakamura T, Ookubo T . Role of IQGAP1, a target of the small GTPases Cdc42 and Rac1, in regulation of E-cadherin- mediated cell-cell adhesion. Science. 1998; 281(5378):832-5. DOI: 10.1126/science.281.5378.832. View

Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J . Estrogen receptors: how do they signal and what are their targets. Physiol Rev. 2007; 87(3):905-31. DOI: 10.1152/physrev.00026.2006. View

Noritake J, Watanabe T, Sato K, Wang S, Kaibuchi K . IQGAP1: a key regulator of adhesion and migration. J Cell Sci. 2005; 118(Pt 10):2085-92. DOI: 10.1242/jcs.02379. View

Kim J, Xu E, Sacks D, Lee J, Shu L, Xia B . Identification and functional studies of a new Nrf2 partner IQGAP1: a critical role in the stability and transactivation of Nrf2. Antioxid Redox Signal. 2012; 19(2):89-101. PMC: 3689176. DOI: 10.1089/ars.2012.4586. View

Yamaoka-Tojo M, Ushio-Fukai M, Hilenski L, Dikalov S, Chen Y, Tojo T . IQGAP1, a novel vascular endothelial growth factor receptor binding protein, is involved in reactive oxygen species--dependent endothelial migration and proliferation. Circ Res. 2004; 95(3):276-83. DOI: 10.1161/01.RES.0000136522.58649.60. View

Jeong H, Li Z, Brown M, Sacks D . IQGAP1 binds Rap1 and modulates its activity. J Biol Chem. 2007; 282(28):20752-62. DOI: 10.1074/jbc.M700487200. View

Clevers H, Nusse R . Wnt/β-catenin signaling and disease. Cell. 2012; 149(6):1192-205. DOI: 10.1016/j.cell.2012.05.012. View

10.

Vasilescu J, Guo X, Kast J . Identification of protein-protein interactions using in vivo cross-linking and mass spectrometry. Proteomics. 2004; 4(12):3845-54. DOI: 10.1002/pmic.200400856. View

11.

White C, Li Z, Dillon D, Sacks D . IQGAP1 protein binds human epidermal growth factor receptor 2 (HER2) and modulates trastuzumab resistance. J Biol Chem. 2011; 286(34):29734-47. PMC: 3191015. DOI: 10.1074/jbc.M111.220939. View

12.

Stanisic V, Lonard D, OMalley B . Modulation of steroid hormone receptor activity. Prog Brain Res. 2010; 181:153-76. DOI: 10.1016/S0079-6123(08)81009-6. View

13.

White C, Brown M, Sacks D . IQGAPs in cancer: a family of scaffold proteins underlying tumorigenesis. FEBS Lett. 2009; 583(12):1817-24. PMC: 2743239. DOI: 10.1016/j.febslet.2009.05.007. View

14.

Manavathi B, Dey O, Gajulapalli V, Bhatia R, Bugide S, Kumar R . Derailed estrogen signaling and breast cancer: an authentic couple. Endocr Rev. 2012; 34(1):1-32. PMC: 3565105. DOI: 10.1210/er.2011-1057. View

15.

Heery D, Kalkhoven E, Hoare S, Parker M . A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature. 1997; 387(6634):733-6. DOI: 10.1038/42750. View

16.

Jadeski L, Mataraza J, Jeong H, Li Z, Sacks D . IQGAP1 stimulates proliferation and enhances tumorigenesis of human breast epithelial cells. J Biol Chem. 2007; 283(2):1008-17. DOI: 10.1074/jbc.M708466200. View

17.

Kumar R, McEwan I . Allosteric modulators of steroid hormone receptors: structural dynamics and gene regulation. Endocr Rev. 2012; 33(2):271-99. PMC: 3596562. DOI: 10.1210/er.2011-1033. View

18.

Aronica S, Katzenellenbogen B . Progesterone receptor regulation in uterine cells: stimulation by estrogen, cyclic adenosine 3',5'-monophosphate, and insulin-like growth factor I and suppression by antiestrogens and protein kinase inhibitors. Endocrinology. 1991; 128(4):2045-52. DOI: 10.1210/endo-128-4-2045. View

19.

HO Y, Joyal J, Li Z, Sacks D . IQGAP1 integrates Ca2+/calmodulin and Cdc42 signaling. J Biol Chem. 1998; 274(1):464-70. DOI: 10.1074/jbc.274.1.464. View

20.

Li Z, Sacks D . Elucidation of the interaction of calmodulin with the IQ motifs of IQGAP1. J Biol Chem. 2002; 278(6):4347-52. DOI: 10.1074/jbc.M208579200. View