Acetylation of the RhoA GEF Net1A controls its subcellular localization and activity

Song, E; Oh, Wonkyung; Ulu, Arzu; Carr, Heather S.; Zuo, Yan; Frost, Jeffrey A.

doi:10.1242/jcs.158121

Cited by 35 publications

(57 citation statements)

References 43 publications

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“…Finally, the sixth group transfer metabolite, acetyl-CoA, is used to acetylate the RhoA-specific GEF partner protein, completing the full panoply of group transfers and exemplifying extensive combinatorial diversification of proteomes 163 . The extent to which any given Rho protein molecule in a cellular population has multiple modifications is not well quantitated nor is the net activity of such multiply-modified Rho species well-evaluated.…”

Section: Intersection and Convergence Of The Posttranslational Momentioning

confidence: 99%

Eight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism

Walsh

Tang³

2017

Chem. Rev.

238

203

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Contemporary analyses of cell metabolism have called out three metabolites: ATP, NADH, and acetyl-CoA, as sentinel molecules whose accumulation represent much of the purpose of the catabolic arms of metabolism and then drive many anabolic pathways. Such analyses largely leave out how and why ATP, NADH, and acetyl-CoA (Figure 1) at the molecular level play such central roles. Yet, without those insights into why cells accumulate them and how the enabling properties of these key metabolites power much of cell metabolism, the underlying molecular logic remains mysterious. Four other metabolites, S-adenosylmethionine, carbamoyl phosphate, UDP-glucose, and Δ2-isopentenyl-PP play similar roles in using group transfer chemistry to drive otherwise unfavorable biosynthetic equilibria. This review provides the underlying chemical logic to remind how these seven key molecules function as mobile packets of cellular currencies for phosphoryl transfers (ATP), acyl transfers (acetyl-CoA, carbamoyl-P), methyl transfers (SAM), prenyl transfers (IPP), glucosyl transfers (UDP-glucose), and electron and ADP-ribosyl transfers (NAD(P)H/NAD(P)+) to drive metabolic transformations in and across most primary pathways. The eighth key metabolite is molecular oxygen (O2), thermodynamically activated for reduction by one electron paths, leaving it kinetically stable to the vast majority of organic cellular metabolites.

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Section: Intersection and Convergence Of The Posttranslational Momentioning

confidence: 99%

Eight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism

Walsh

Tang³

2017

Chem. Rev.

238

203

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“…MYC-nick associates with acetyltransferase and induces acetylation of several cytoplasmic proteins, among which we characterized α-tubulin and ATG3 (15,16). We speculate that MYCnick binding and acetylation of cytoplasmic factors, such as specific GAPs or GEFs, could account for modulation of Cdc42 activity by MYC-nick (45). Similarly, MYC-nick may influence cytoplasmic signaling to the nucleus, or perhaps itself serve as a transcriptional cofactor, leading to the expression of fascin or other genes.…”

Section: Discussionmentioning

confidence: 93%

“…Fascin and Cdc42 function in coordination to promote filopodia formation and to drive cell migration (43)(44)(45). Moreover, Cdc42 was shown to regulate fascin localization and function.…”

Section: Induction Of Fascin and Activation Of Cdc42 By Myc-nick Arementioning

confidence: 99%

MYC-nick promotes cell migration by inducing fascin expression and Cdc42 activation

Anderson

Poudel

Roh-Johnson

et al. 2016

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

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MYC-nick is a cytoplasmic, transcriptionally inactive member of the MYC oncoprotein family, generated by a proteolytic cleavage of full-length MYC. MYC-nick promotes migration and survival of cells in response to chemotherapeutic agents or withdrawal of glucose. Here we report that MYC-nick is abundant in colonic and intestinal tumors derived from mouse models with mutations in the Wnt, TGF-β, and PI3K pathways. Moreover, MYC-nick is elevated in colon cancer cells deleted for FBWX7, which encodes the major E3 ligase of full-length MYC frequently mutated in colorectal cancers. MYC-nick promotes the migration of colon cancer cells assayed in 3D cultures or grown as xenografts in a zebrafish metastasis model. MYC-nick accelerates migration by activating the Rho GTPase Cdc42 and inducing fascin expression. MYC-nick, fascin, and Cdc42 are frequently up-regulated in cells present at the invasive front of human colorectal tumors, suggesting a coordinated role for these proteins in tumor migration. (9). As one of the major determinants of MYC's transcriptional function, MBII recruits coactivator complexes including histone acetyltransferases (HATs), such as GCN5 (10) and Tip60 (11). MYC is a very short-lived protein, and multiple E3 ligases have been implicated in regulating MYC protein turnover through the ubiquitin-proteasome system (12). Importantly, MYC levels have been demonstrated to be elevated in cancer cells because of prolonged protein halflife (13,14).MYC is also targeted by calpain proteases in the cytoplasm (15-17). Calpain-mediated scission of MYC degrades its C terminus, which inactivates MYC's transcriptional functions. Furthermore, the cleavage generates MYC-nick, a truncated product that retains MBI-MBIII (16). Although MYC-nick is expressed in most cultured cells and in mouse tissues, its levels are increased in cells cultured under conditions leading to stress, such as high cell density, nutrient deprivation, and hypoxia (15,16,18). Recently, we found that the conversion of MYC into MYC-nick occurs in the cytoplasm of colon cancer cells, where it promotes cell survival and motility (15). Here we demonstrate that MYC-nick promotes cell migration and invasion by inducing fascin expression and activating the Rho GTPase Cdc42 in distinct models of colon cancer. Results MYC-Nick Is Expressed in Intestinal and Colon Lesions in MouseCancer Models Driven by Mutations in Apc, Tgfbr2, and Kras. We had previously shown that MYC-nick is expressed in cancer cell lines and cancers arising from different primary tissues (15). To extend those studies, we examined the expression of MYC variants in mouse colon cancers derived from distinct models of intestinal cancer. Most colorectal carcinomas carry mutations that affect Wnt, TGF-β, and PI3K signaling pathways (19,20). We compared the expression of MYC in tumors arising from models containing (i) a truncation in one of the alleles of Apc (Apc 1638/+ ; labeled ATT); (ii) Pten and Tgfbr2 deletions combined (PPVcTT); (iii) Apc truncation in combination with Tgfbr2 dele...

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“…Previous work has shown that acetylation can promote E3 ligase-mediated ubiquitination in multiple proteins subject to rapid turnover (Jiang et al, 2011; Liu et al, 2013b; Wang et al, 2012). In some contexts, acetylation also regulates subcellular localization to facilitate proteasomal degradation of the target protein (Fujita et al, 2015; Song et al, 2015). Future studies are needed to fully understand how acetylation is integrated into the regulatory network regulating Slug abundance and its downstream biological effects.…”

Section: Discussionmentioning

confidence: 99%

The SIRT2 Deacetylase Stabilizes Slug to Control Malignancy of Basal-like Breast Cancer

Zhou

Wronski

et al. 2016

Cell Reports

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Summary Overabundance of Slug protein is common in human cancer and represents an important determinant underlying the aggressiveness of basal-like breast cancer (BLBC). Despite its importance, this transcription factor is rarely mutated in BLBC, and the mechanism of its deregulation in cancer remains unknown. Here we report that Slug undergoes acetylation-dependent protein degradation and identify the deacetylase SIRT2 as a key mediator of this post-translational mechanism. SIRT2 inhibition rapidly destabilizes Slug, whereas SIRT2 overexpression extends Slug stability. We show that SIRT2 deacetylates Slug protein at lysine residue K116 to prevent Slug degradation. Interestingly, SIRT2 is frequently amplified and highly expressed in BLBC. Genetic depletion and pharmacological inactivation of SIRT2 in BLBC cells reverse Slug stabilization, cause the loss of clinically relevant pathological features of BLBC, and inhibit tumor growth. Our results suggest that targeting SIRT2 may be a rational strategy for diminishing Slug abundance and its associated malignant traits in BLBC.

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Acetylation of the RhoA GEF Net1A controls its subcellular localization and activity

Cited by 35 publications

References 43 publications

Eight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism

Eight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism

MYC-nick promotes cell migration by inducing fascin expression and Cdc42 activation

The SIRT2 Deacetylase Stabilizes Slug to Control Malignancy of Basal-like Breast Cancer

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