E3 Ubiquitin Ligase, WWP1, Interacts with AMPKα2 and Down-regulates Its Expression in Skeletal Muscle C2C12 Cells

Lee, Jung Ok; Lee, Soo Kyung; Kim, Nami; Kim, Ji Hae; You, Ga Young; Moon, Ji Wook; Sha, Jie; Kim, Su Jin; Lee, Yong Woo; Kang, Hoyoul; Lim, Yongchul; Park, Sun Hwa; Kim, Hyeon Soo

doi:10.1074/jbc.m112.406009

Cited by 26 publications

(28 citation statements)

References 32 publications

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“…Previous reports have shown that Gremlin-1 expression can also be stimulated by increasing glucose levels (Gremlin-1 was once termed increased-in-high-glucoseprotein-2) (58). This is consistent with the effect of glucose on Smurf-1 ( Figure 5) and other ubiquitin ligases (59), as well as with the role of hyperglycemia on Gremlin-1 in podocyte injury (60) and cell proliferation in mesangial cells (61). It is possible that Smurf-1 is regulated by glucose uptake/metabolism by mechanisms similar to those of Gremlin-1, in which transforming growth factor b-1 (TGFb-1) signaling pathways are amplified (60,62).…”

Section: Original Researchsupporting

confidence: 68%

Bone Morphogenic Protein Type 2 Receptor Mutation-Independent Mechanisms of Disrupted Bone Morphogenetic Protein Signaling in Idiopathic Pulmonary Arterial Hypertension

Barnes¹,

Kucera²,

Tian³

et al. 2016

Am J Respir Cell Mol Biol

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Altered bone morphogenic protein (BMP) signaling, independent of BMPR2 mutations, can result in idiopathic pulmonary arterial hypertension (IPAH). Glucose dysregulation can regulate multiple processes in IPAH. However, the role of glucose in BMP antagonist expression in IPAH has not been characterized. We hypothesized that glucose uptake regulates BMP signaling through stimulation of BMP antagonist expression in IPAH. Using human plasma, lung tissue, and primary pulmonary arterial smooth muscle cells (PASMCs), we examined the protein expression of BMP2, BMP-regulated Smads, and Smurf-1 in patients with IPAH and control subjects. Gremlin-1 levels were elevated in patients with IPAH compared with control subjects, whereas expression of BMP2 was not different. We demonstrate increased Smad polyubiquitination in IPAH lung tissue and PASMCs that was further enhanced with proteasomal inhibition. Examination of the Smad ubiquitin-ligase, Smurf-1, showed increased protein expression in IPAH lung tissue and localization in the smooth muscle of the pulmonary artery. Glucose dose dependently increased Smurf-1 protein expression in control PASMCs, whereas Smurf-1 in IPAH PASMCs was increased and sustained. Conversely, phosphoSmad1/5/8 levels were reduced in IPAH compared with control PASMCs at physiological glucose concentrations. Interestingly, high glucose concentrations decreased phosphorylation of Smad1/5/8 in control PASMCs. Blocking glucose uptake had opposing effects in IPAH PASMCs, and inhibition of Smurf-1 activity resulted in partial rescue of Smad1/5/8 activation and cell migration rates. Collectively, these data suggest that BMP signaling can be regulated through BMPR2 mutation-independent mechanisms. Gremlin-1 (synonym: induced-in-high-glucose-2 protein) and Smurf-1 may function to inhibit BMP signaling as a consequence of the glucose dysregulation described in IPAH.

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Section: Original Researchsupporting

confidence: 68%

Bone Morphogenic Protein Type 2 Receptor Mutation-Independent Mechanisms of Disrupted Bone Morphogenetic Protein Signaling in Idiopathic Pulmonary Arterial Hypertension

Barnes¹,

Kucera²,

Tian³

et al. 2016

Am J Respir Cell Mol Biol

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“…AMPKα2 levels in mouse myoblast cells are similarly down-regulated in response to glucose by the Ubiquitin E3-ligase Wwp1 (62).…”

Section: Discussionmentioning

confidence: 85%

SUMOylation regulates the SNF1 protein kinase

Simpson-Lavy

Johnston

2013

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

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The AMP-activated protein kinase (AMPK) is a major stress sensor of mammalian cells. AMPK's homolog in the yeast Saccharomyces cerevisiae, the SNF1 protein kinase, is a central regulator of carbon metabolism that inhibits the Snf3/Rgt2-Rgt1 glucose sensing pathway and activates genes involved in respiration. We present evidence that glucose induces modification of the Snf1 catalytic subunt of SNF1 with the small ubiquitin-like modifier protein SUMO, catalyzed by the SUMO (E3) ligase Mms21. Our results suggest that SUMOylation of Snf1 inhibits its function in two ways: by interaction of SUMO attached to lysine 549 with a SUMO-interacting sequence motif located near the active site of Snf1, and by targeting Snf1 for destruction via the Slx5-Slx8 (SUMO-directed) ubiquitin ligase. These findings reveal another way SNF1 function is regulated in response to carbon source.protein kinase regulation | protein modification | signal transduction G lucose is the preferred carbon source of most cells, including Saccharomyces cerevisiae, which ferments it to ethanol and CO 2 , producing only two ATPs, even when oxygen is available to drive production of much more ATP. This preference for fermentation (which cancer cells share), is known as the Crabtree or Warburg effect (1, 2). Because of the energetic inefficiency of fermentation, yeast cells must be adroit in sensing glucose. S. cerevisiae has three well-known glucose sensing pathways: (i) the Gpa1/2-Ras2-PKA pathway that regulates stress response (through Msn2/4) and other things; (ii) the SNF1 pathway, which regulates respiratory metabolism and other processes; and (iii) the Snf3/Rgt2-Rgt1 (SRR) pathway that regulates expression of genes encoding hexose transporters (3).The SRR (sensor/receptor-repressor) pathway begins at the cell surface with high-affinity (Snf3) (4) and low-affinity (Rgt2) glucose sensors (5) that are coupled to the casein kinases Yck1 and Yck2, which catalyze phosphorylation of the corepressor proteins Mth1 and Std1 (6), leading to their ubiquitinylation by SCF Grr1 (7,8). The subsequent destruction of Mth1 and Std1 inactivates the Rgt1 transcriptional repressor, resulting in derepression of HXT genes encoding hexose transporters (7, 9). In response to glucose, Yck1/2 also mediates inactivation and degradation of transporters of alternative carbon sources, such as maltose (Mal61) (10) and lactate/pyruvate/acetate (Jen1) (11). Achieving this glucose-induced switching of transporters seems to be the main purpose of the SRR pathway (12).The SNF1 protein kinase-the ortholog of the AMP-activated protein kinase (AMPK), a major stress-activated protein kinase in mammalian cells (13,14)-is a central regulator of carbon metabolism (15,16). This kinase is an activator of Adr1 and Cat8, which activate expression of genes involved in the diauxic shift, ethanol, and lactate uptake and catabolism, gluconeogenesis, and respiration (17-21), and is an inhibitor of the Mig1 repressor of glucose-repressed genes (22). SNF1 is a heterotrimer of the Snf1 catalytic subunit,...

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“…Under energy stress, USP10 removes the ubiquitination of AMPKα and expose AMPKα to LKB1. Recent studies have also shown that ubiquitination of AMPKα could mediate its degradation under certain conditions (Lee et al, 2013; Pineda et al, 2015). However, in our experimental systems, the ubiquitination of AMPKα does not affect its protein level.…”

Section: Discussionmentioning

confidence: 99%

Deubiquitination and Activation of AMPK by USP10

et al. 2016

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The AMP-activated protein kinase (AMPK) is the master regulator of metabolic homeostasis by sensing cellular energy status. When intracellular ATP levels decrease during energy stress, AMPK is initially activated through AMP or ADP binding and phosphorylation of a threonine residue (Thr-172) within the activation loop of its kinase domain. Here we report a key molecular mechanism by which AMPK activation is amplified under energy stress. We found that ubiquitination on AMPKα blocks AMPKα phosphorylation by LKB1. The deubiquitinase USP10 specifically removes ubiquitination on AMPKα to facilitate AMPKα phosphorylation by LKB1. Under energy stress, USP10 activity in turn is enhanced through AMPK-mediated phosphorylation of Ser76 of USP10. Thus, USP10 and AMPK form a key feedforward loop ensuring amplification of AMPK activation in response to fluctuation of cellular energy status. Disruption of this feedforward loop leads to improper AMPK activation and multiple metabolic defects.

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E3 Ubiquitin Ligase, WWP1, Interacts with AMPKα2 and Down-regulates Its Expression in Skeletal Muscle C2C12 Cells

Cited by 26 publications

References 32 publications

Bone Morphogenic Protein Type 2 Receptor Mutation-Independent Mechanisms of Disrupted Bone Morphogenetic Protein Signaling in Idiopathic Pulmonary Arterial Hypertension

Bone Morphogenic Protein Type 2 Receptor Mutation-Independent Mechanisms of Disrupted Bone Morphogenetic Protein Signaling in Idiopathic Pulmonary Arterial Hypertension

SUMOylation regulates the SNF1 protein kinase

Deubiquitination and Activation of AMPK by USP10

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