Rho Family Guanine Nucleotide Exchange Factor Brx Couples Extracellular Signals to the Glucocorticoid Signaling System

Kino, Tomoshige; Souvatzoglou, Emanuel; Charmandari, Evangelia; Ichijo, Takamasa; Driggers, Paul H.; Mayers, C.; Alatsatianos, Anton; Manoli, Irini; Westphal, Heiner; Chrousos, George P.; Segars, James H.

doi:10.1074/jbc.m509339200

Cited by 41 publications

(39 citation statements)

References 48 publications

(55 reference statements)

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“…For example, the GEF protein Brx interacts directly with and enhances the transcriptional activity of ERa (Rubino et al 1998) and the glucocorticoid receptor (Kino et al 2006). Vav3, another GEF protein, increases AR-mediated transactivation, but does not appear to interact with the receptor (Lyons & Burnstein 2006).…”

Section: Discussionmentioning

confidence: 99%

Rho GDP dissociation inhibitor α interacts with estrogen receptor α and influences estrogen responsiveness

Marzouk

Schultz-Norton

Likhite

et al. 2007

Journal of Molecular Endocrinology

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Estrogen receptor a (ERa) is a ligand-activated transcription factor that regulates expression of estrogen-responsive genes. Upon binding of the ligand-occupied ERa to estrogen response elements (EREs) in DNA, the receptor interacts with a variety of coregulatory proteins to modulate transcription of target genes. We have isolated and identified a number of proteins associated with the DNA-bound ERa. One of these proteins, Rho guanosine diphosphate (GDP) dissociation inhibitor a (RhoGDIa), is a negative regulator of the Rho family of GTP-binding proteins. In this study, we demonstrate that endogenously expressed RhoGDIa is present in the nucleus as well as the cytoplasm of MCF-7 breast cancer cells, and that RhoGDIa binds directly to ERa, alters the ERa-ERE interaction, and influences the ability of ERa to regulate transcription of a heterologous estrogen-responsive reporter plasmid in transient transfection assays as well as endogenous, estrogen-responsive genes in MCF-7 cells. Our studies suggest that, in addition to the activity of RhoGDIa in the cytoplasm, it also influences ERa signaling in the nucleus.

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Section: Discussionmentioning

confidence: 99%

Rho GDP dissociation inhibitor α interacts with estrogen receptor α and influences estrogen responsiveness

Marzouk

Schultz-Norton

Likhite

et al. 2007

Journal of Molecular Endocrinology

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“…Brx) because our prior studies of AKAP13 had focused on its ability to augment estrogen 29,31 and glucocorticoid action. 37 We were intrigued by the fact that sex steroids influence leiomyoma growth, but conversely excessive glucocorticoids (such as Cushing's Sydrome) cause muscle atrophy. Since the microarray results singled out this transcript, we proceeded to characterize expression of AKAP13 in leiomyoma.…”

Section: Commentmentioning

confidence: 99%

Mechanical homeostasis is altered in uterine leiomyoma

Rogers

Norian

Malik

et al. 2008

American Journal of Obstetrics and Gynecology

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Objective-Uterine leiomyoma produce an extracellular matrix (ECM) that is abnormal in its volume, content, and structure. Alterations in ECM can modify mechanical stress on cells, leading to activation of Rho-dependent signaling. Here we sought to determine whether the altered ECM produced by leiomyoma was accompanied by an altered state of mechanical homeostasis.Study Design-Measurement of the mechanical response in paired leiomyoma and myometrium, immunogold, confocal microscopy, and immunohistochemical analyses.Results-Leiomyoma were significantly stiffer than matched myometrium. The increased stiffness was associated with a moderate increase in total sulfated glycosaminoglycan content and a slight increase in hydroxyproline. Levels of the Rho-GEF, AKAP13, were increased and subcellular localization was altered in leiomyoma. Phosphorylation of p38MAPK was greater in leiomyoma extracts. Conclusions-Leiomyoma

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“…The carboxyl region of the brx-1 transcript encoded an LXXLL nuclear receptor-interacting domain, and BRX-1 protein was found to specifically interact with nuclear hormone receptors (1,14,15). Homodimerization of the carboxyl region has been reported to regulate Rho-GEF activity of the protein (16).…”

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confidence: 99%

“…AKAP13 proteins have been shown to coordinate signals originating from the cell membrane, including thrombin (17), lysophosphatidic acid (LPA) receptors (3,15), and the osmoreceptor (18). Specifically, AKAP13 proteins have been shown to interact with G␣ 12 (3,17), G␣ 13 (19), G␣ 14 (20), G q (19 -21), and possibly G␣ 15 (15). Despite considerable evidence suggesting the importance of AKAP13 in vitro, the in vivo role of the protein has remained unclear.…”

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confidence: 99%

“…The brx-1 transcript (1) encodes the smallest naturally occurring protein of AKAP13, due to an abbreviated AKAP domain (3). AKAP13 proteins have been shown to coordinate signals originating from the cell membrane, including thrombin (17), lysophosphatidic acid (LPA) receptors (3,15), and the osmoreceptor (18). Specifically, AKAP13 proteins have been shown to interact with G␣ 12 (3, 17), G␣ 13 (19), G␣ 14 (20), G q (19 -21), and possibly G␣ 15 (15).…”

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confidence: 99%

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The Rho Guanine Nucleotide Exchange Factor AKAP13 (BRX) Is Essential for Cardiac Development in Mice

Mayers

Wadell

McLean

et al. 2010

Journal of Biological Chemistry

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A fundamental biologic principle is that diverse biologic signals are channeled through shared signaling cascades to regulate development. Large scaffold proteins that bind multiple proteins are capable of coordinating shared signaling pathways to provide specificity to activation of key developmental genes. Although much is known about transcription factors and target genes that regulate cardiomyocyte differentiation, less is known about scaffold proteins that couple signals at the cell surface to differentiation factors in developing heart cells. Here we show that AKAP13 (also known as Brx-1, AKAP-Lbc, and proto-Lbc), a unique protein kinase A-anchoring protein (AKAP) guanine nucleotide exchange region belonging to the Dbl family of oncogenes, is essential for cardiac development. Cardiomyocytes of Akap13-null mice had deficient sarcomere formation, and developing hearts were thin-walled and mice died at embryonic day 10.5-11.0. Disruption of Akap13 was accompanied by reduced expression of Mef2C. Consistent with a role of AKAP13 upstream of MEF2C, Akap13 siRNA led to a reduction in Mef2C mRNA, and overexpression of AKAP13 augmented MEF2C-dependent reporter activity. The results suggest that AKAP13 coordinates G␣ 12 and Rho signaling to an essential transcription program in developing cardiomyocytes.We previously reported cloning and characterization of a human 5.3-kb brx-1 (breast cancer nuclear hormone receptor auxiliary factor 1) transcript that encoded a 170-kDa Dbl family member (1) and later localized the gene to chromosome 15q24-25 (2). Larger transcripts of the gene were subsequently isolated (3), and based on its AKAP region, the gene we initially called BRX is now known as AKAP13.The central Dbl homology (DH) 3 or guanine nucleotide exchange region (GEF) is present in all native transcripts of AKAP13 (Fig. 1). The lbc oncogene (4), derived from two chromosomes, 15 and 7 (5), contains the GEF region of AKAP13 but lacks the N terminus and carboxyl regions. The GEF domain of AKAP13 was shown to bind RhoA and activate Rho family GTPases (3, 5, 6). Rho GTPases have been reported to influence the cell cytoskeleton and sarcomere development in cardiomyocytes (7-9). RhoA, a target of AKAP13, influences at least 11 downstream effectors (10), including two factors essential for cardiomyocyte differentiation, serum response factor (SRF) and 11,12). AKAP13 was also shown to play a role in cardiac hypertrophy (13) via MEF2 (myocyte enhancer factor-2). Despite the established role for RhoA in cardiac development, the importance of AKAP13 in the developing heart has not been described.The function of the carboxyl region of proteins encoded by AKAP13 has remained enigmatic. The carboxyl region of the brx-1 transcript encoded an LXXLL nuclear receptor-interacting domain, and BRX-1 protein was found to specifically interact with nuclear hormone receptors (1, 14, 15). Homodimerization of the carboxyl region has been reported to regulate Rho-GEF activity of the protein (16). These observations suggest that the carboxyl r...

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Rho Family Guanine Nucleotide Exchange Factor Brx Couples Extracellular Signals to the Glucocorticoid Signaling System

Cited by 41 publications

References 48 publications

Rho GDP dissociation inhibitor α interacts with estrogen receptor α and influences estrogen responsiveness

Rho GDP dissociation inhibitor α interacts with estrogen receptor α and influences estrogen responsiveness

Mechanical homeostasis is altered in uterine leiomyoma

The Rho Guanine Nucleotide Exchange Factor AKAP13 (BRX) Is Essential for Cardiac Development in Mice

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