Selective role for RGS12 as a Ras/Raf/MEK scaffold in nerve growth factor-mediated differentiation

Willard, Melinda D.; Willard, Francis S.; Li, Xiaoyan; Cappell, Steven D.; Snider, William D.; Siderovski, David P.

doi:10.1038/sj.emboj.7601659

Cited by 76 publications

(101 citation statements)

References 74 publications

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“…In the case of the MAPK pathway, it has been reported that scaffold proteins promote the formation of complexes containing receptors (30,50). Here we showed that Freud-1/Aki1 interacts with PDK1 and Akt and regulates Akt activation upon EGF signaling by functioning as a scaffold.…”

Section: Identification Of the Domains Responsible For Interactions Ofmentioning

confidence: 61%

“…As the scaffold, Freud-1/Aki1 specifically and effectively activates Akt among several PDK1 substrates. Moreover, in the case of the MAPK pathway, it has been reported that scaffold proteins form complexes with receptors (30,50). An interesting observation is that increased interactions of Freud-1/Aki1 with EGFR and Akt occurred after EGF stimulation, whereas interactions of Freud-1/Aki1 with IGF-1R and Akt were not detected after IGF-1 stimulation.…”

Section: Discussionmentioning

confidence: 99%

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Freud-1/Aki1, a Novel PDK1-Interacting Protein, Functions as a Scaffold To Activate the PDK1/Akt Pathway in Epidermal Growth Factor Signaling

Nakamura

Naito

Tsuruo

et al. 2008

Molecular and Cellular Biology

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The phosphoinositide 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathway regulates various cellular functions, especially cell survival and cell cycle progression. In contrast to other survival pathways, there have been few reports of scaffold proteins that regulate signaling cascade specificity in this pathway. Here we identify a 5 repressor element under dual-repression binding protein 1 (Freud-1)/Akt kinase-interacting protein 1 (Aki1) as a novel scaffold for the PDK1/Akt pathway. Freud-1/Aki1 (also known as CC2D1A) expression induced formation of a PDK1/Akt complex and regulated Akt activation in a concentration-dependent biphasic manner. Freud-1/Aki1 also associated with epidermal growth factor (EGF) receptor in response to EGF stimulation and was required for Akt activation induced by EGF, but not by insulin-like growth factor 1. Freud-1/Aki1 gene silencing decreased Akt kinase activity, resulting in induction of apoptosis and increased sensitivity toward chemotherapeutic agents. Our results suggest that Freud-1/Aki1 is a novel receptor-selective scaffold protein for the PDK1/Akt pathway and present a new activation mechanism of Akt.

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Section: Identification Of the Domains Responsible For Interactions Ofmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Freud-1/Aki1, a Novel PDK1-Interacting Protein, Functions as a Scaffold To Activate the PDK1/Akt Pathway in Epidermal Growth Factor Signaling

Nakamura

Naito

Tsuruo

et al. 2008

Molecular and Cellular Biology

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“…The R7 subfamily of RGS6, -7, -9, and -11 form dimers with G␤5 (9) via a G␥-like domain N-terminal to their RGS domain. The R12 subfamily constitutes RGS10, -12, and -14, with the latter two sharing additional domains reflecting unique roles as Ras/Raf/ MAPK scaffolds (10). The other four subfamilies are signaling regulators that have since become associated with the RGS protein superfamily (5,11) upon discovery of more distantly related RGS domains within them (i.e., Axin, Axil; RhoGEFs p115-RhoGEF, LARG, and PDZ-RhoGEF; the sorting nexins SNX13, -14, and -25; the GPCR kinases GRK1-7).…”

mentioning

confidence: 99%

Structural diversity in the RGS domain and its interaction with heterotrimeric G protein α-subunits

Soundararajan

Willard

Kimple

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

187

239

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Regulator of G protein signaling (RGS) proteins accelerate GTP hydrolysis by G␣ subunits and thus facilitate termination of signaling initiated by G protein-coupled receptors (GPCRs). RGS proteins hold great promise as disease intervention points, given their signature role as negative regulators of GPCRs-receptors to which the largest fraction of approved medications are currently directed. RGS proteins share a hallmark RGS domain that interacts most avidly with G␣ when in its transition state for GTP hydrolysis; by binding and stabilizing switch regions I and II of G␣, RGS domain binding consequently accelerates G␣-mediated GTP hydrolysis. The human genome encodes more than three dozen RGS domaincontaining proteins with varied G␣ substrate specificities. To facilitate their exploitation as drug-discovery targets, we have taken a systematic structural biology approach toward cataloging the structural diversity present among RGS domains and identifying molecular determinants of their differential G␣ selectivities. Here, we determined 14 structures derived from NMR and x-ray crystallography of members of the R4, R7, R12, and RZ subfamilies of RGS proteins, including 10 uncomplexed RGS domains and 4 RGS domain/G␣ complexes. Heterogeneity observed in the structural architecture of the RGS domain, as well as in engagement of switch III and the all-helical domain of the G␣ substrate, suggests that unique structural determinants specific to particular RGS protein/G␣ pairings exist and could be used to achieve selective inhibition by small molecules.GTPase-accelerating proteins ͉ NMR structure ͉ RGS proteins ͉ x-ray crystallography G protein-coupled receptors (GPCRs) are critical for many physiological processes including vision, olfaction, neurotransmission, and the actions of many hormones (1). As such, GPCRs are the largest fraction of the ''druggable proteome,'' and their ligand-binding and signaling properties remain of considerable interest to academia and industry (2). GPCRs catalyze activation of heterotrimeric G proteins comprising a guanine nucleotide-binding G␣ subunit and an obligate G␤␥ dimer (3). Receptor-promoted activation of G␣␤␥ causes exchange of GDP for GTP by G␣ and resultant dissociation of G␤␥. GTP-bound G␣ and freed G␤␥ then regulate intracellular effectors such as adenylyl cyclase, phospholipase C, ion channels, RhoGEFs, and phosphodiesterases (1, 4). This ''G protein cycle'' is reset by the intrinsic GTP hydrolysis activity of G␣, producing G␣⅐GDP that favors heterotrimer reformation and, consequently, signal termination. Thus, a major determinant of the duration and magnitude of GPCR signaling is the lifetime of G␣ in the GTP-bound state.Regulators of G protein signaling are GTPase-accelerating proteins (GAPs) for G␣ subunits and thus facilitate GPCR signal termination (5). GAP activity is conferred by an RGS domain present in one or more copies within members of this protein superfamily (5). The archetypal RGS domain is composed of nine ␣-helices (6) and binds most avidly to G␣ in the transi...

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“…These results were in agreement with the previous report that RGS12 serves as a Ras/Raf/MEK scaffold to accelerate ERK1/2 activation during neuronal differentiation. 21 Furthermore, the requirement of the MEK1/2-ERK1/2 signaling for RGS12-exacerbated cardiac hypertrophy and heart failure was validated by the rescue experiments using the MEK1/2-specific inhibitor U0126. On one hand, activated ERK1/2 translocate to the nucleus and thus phosphorylate transcription factors, such as Elk-1 and GATA4, resulting in the hypertrophic gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…18 Huang et al 20 reported that RGS12 inactivates phosphorylated Gαi to ameliorate the inhibition of cAMP formation and thus facilitates muscle relaxation. In addition, Willard et al 21 found that RGS12 serves as a scaffold and organizes Abstract-Cardiac hypertrophy is a major predictor of heart failure and is regulated by diverse signaling pathways. As a typical multi-domain member of the regulator of G-protein signaling (RGS) family, RGS12 plays a regulatory role in various signaling pathways.…”

mentioning

confidence: 99%

Pivotal Role of Regulator of G-protein Signaling 12 in Pathological Cardiac Hypertrophy

et al. 2016

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Cardiac hypertrophy is initially an adaptive response to cardiac stresses, including mechanical overload, ischemia, and endocrine disorders.1,2 At the beginning, it elicits beneficial effects by reducing ventricular wall stress and maintaining cardiac output without adverse pathology. However, sustained hypertrophy of the myocardium can progress into a decompensated state that is characterized by fetal gene expression, contractile dysfunction, and extracellular remodeling, eventually leading to heart failure. 3,4 During this complicated process, specific signaling pathways mediate the critical transition from compensated hypertrophy to decompensated hypertrophy and heart failure. 5,6 Therefore, a better understanding of the molecular mechanisms regulating the hypertrophy-related signaling pathways is important for the development of new strategies to treat pathological cardiac hypertrophy and heart failure.Regulator of G-protein signaling (RGS) proteins represent a family of proteins originally defined by the presence of a semiconserved region of ≈120 amino acids called the RGS domain. They function as GTPase-activating proteins for Gα proteins to repress G-protein-coupled receptor signaling. 7,8 To date, several members of the RGS family have been found to participate in pathological cardiac hypertrophy. [9][10][11][12][13] Recently, a growing number of studies demonstrated that RGS proteins could regulate cardiac hypertrophy independent of GTPaseactivating protein activity. Among them, RGS3, RGS5, and RGS10 protect against pressure overload-induced hypertrophic response and improve cardiac function by inhibiting MEK1/2-ERK1/2 signaling. 11,13,14 RGS12 is the largest, typical multidomain member of the RGS family. 15 In addition to a central RGS domain, RGS12 contains a PDZ (PSD-95/ discslarge/ZO-1 homology) domain, with putative CXCR2-binding properties, and a phosphotyrosine-binding domain at the N terminus, whereas a tandem repeat of Ras-binding domains and a Gai/o-Loco motif are located at the C terminus of RGS12. [16][17][18][19] This multidomain architecture contributes to the regulatory role of RGS12 in diverse signaling pathways. 18 Huang et al 20 reported that RGS12 inactivates phosphorylated Gαi to ameliorate the inhibition of cAMP formation and thus facilitates muscle relaxation. In addition, Willard et al 21 found that RGS12 serves as a scaffold and organizes Abstract-Cardiac hypertrophy is a major predictor of heart failure and is regulated by diverse signaling pathways. As a typical multi-domain member of the regulator of G-protein signaling (RGS) family, RGS12 plays a regulatory role in various signaling pathways. However, the precise effect of RGS12 on cardiac hypertrophy remains largely unknown.In this study, we observed increased expression of RGS12 in the development of pathological cardiac hypertrophy and heart failure. We then generated genetically engineered mice and neonatal rat cardiomyocytes to investigate the effects of RGS12 during this pathological process. P<0.05). RGS12 also contri...

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Selective role for RGS12 as a Ras/Raf/MEK scaffold in nerve growth factor-mediated differentiation

Cited by 76 publications

References 74 publications

Freud-1/Aki1, a Novel PDK1-Interacting Protein, Functions as a Scaffold To Activate the PDK1/Akt Pathway in Epidermal Growth Factor Signaling

Freud-1/Aki1, a Novel PDK1-Interacting Protein, Functions as a Scaffold To Activate the PDK1/Akt Pathway in Epidermal Growth Factor Signaling

Structural diversity in the RGS domain and its interaction with heterotrimeric G protein α-subunits

Pivotal Role of Regulator of G-protein Signaling 12 in Pathological Cardiac Hypertrophy

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