Smurf E3 ubiquitin ligases at the cross roads of oncogenesis and tumor suppression

David, Diana; Nair, S. Asha; Pillai, M. Radhakrishna

doi:10.1016/j.bbcan.2012.11.003

Cited by 71 publications

(92 citation statements)

References 88 publications

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“…Gremlin-1 has been shown to antagonize BMP signaling directly through intracellular and/or extracellular mechanisms, including reducing BMP/BMP receptor interactions (52,53). Furthermore, regulation of BMP signaling through indirect mechanisms such as Smurf-1 ubiquitination of receptorregulated Smads has been shown (24). Many biological functions involving Smurf-1 and Gremlin-1 inhibition of BMP signaling, including cell growth, differentiation, adhesion, and migration, have been analyzed (23,24,34,45,46,(51)(52)(53)(54).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, regulation of BMP signaling through indirect mechanisms such as Smurf-1 ubiquitination of receptorregulated Smads has been shown (24). Many biological functions involving Smurf-1 and Gremlin-1 inhibition of BMP signaling, including cell growth, differentiation, adhesion, and migration, have been analyzed (23,24,34,45,46,(51)(52)(53)(54). These BMP antagonists have been shown to promote the proliferation of cancer cells similar to the proproliferative state demonstrated in PAH (55).…”

Section: Discussionmentioning

confidence: 99%

“…Past reports define significant roles for Gremlin-1 and Smurf-1 in the regulation of several processes, including cell differentiation and proliferation (23)(24)(25)(26). The roles of these BMP antagonists in diseases such as diabetes, liver fibrosis, cancer, and right ventricular hypertrophy and failure demonstrate their importance in disease pathophysiology (27)(28)(29)(30).…”

Section: Pulmonary Arterial Hypertension (Pah)mentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Pulmonary Arterial Hypertension (Pah)mentioning

confidence: 99%

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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

View full text Add to dashboard Cite

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“…Increasing evidence shows that it is involved in multiple biological processes (16,31). In this context, we investigated the functions of Smurf2 in RLR-mediated antiviral signaling.…”

Section: Isg15mentioning

confidence: 99%

“…Smurfs contain an N-terminal C2 domain for membrane binding, a central region containing two or three WW domains for protein-protein interaction, and a C-terminal HECT domain for ubiquitin protein ligation (16). They were first implicated in Smad degradation.…”

mentioning

confidence: 99%

Smurf2 Negatively Modulates RIG-I–Dependent Antiviral Response by Targeting VISA/MAVS for Ubiquitination and Degradation

Pan

Meng

et al. 2014

The Journal of Immunology

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VISA (also known as MAVS, Cardif, IPS-1) is the essential adaptor protein for virus-induced activation of IFN regulatory factors 3 and 7 and production of type I IFNs. Understanding the regulatory mechanisms for VISA will provide detailed insights into the positive or negative regulation of innate immune responses. In this study, we identified Smad ubiquitin regulatory factor (Smurf) 2, one of the Smad ubiquitin regulator factor proteins, as an important negative regulator of virus-triggered type I IFN signaling, which targets at the VISA level. Overexpression of Smurf2 inhibits virus-induced IFN-β and IFN-stimulated response element activation. The E3 ligase defective mutant Smurf2/C716A loses the ability to suppress virus-induced type I IFN signaling, suggesting that the negative regulation is dependent on the ubiquitin E3 ligase activity of Smurf2. Further studies demonstrated that Smurf2 interacted with VISA and targeted VISA for K48-linked ubiquitination, which promoted the degradation of VISA. Consistently, knockout or knockdown of Smurf2 expression therefore promoted antiviral signaling, which was correlated with the increase in protein stability of VISA. Our findings suggest that Smurf2 is an important nonredundant negative regulator of virus-triggered type I IFN signaling by targeting VISA for K48-linked ubiquitination and degradation.

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Inhibition of RNF6 alleviates traumatic brain injury by suppressing STAT3 signaling in rats

et al. 2020

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Smurf E3 ubiquitin ligases at the cross roads of oncogenesis and tumor suppression

Cited by 71 publications

References 88 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

Smurf2 Negatively Modulates RIG-I–Dependent Antiviral Response by Targeting VISA/MAVS for Ubiquitination and Degradation

Inhibition of RNF6 alleviates traumatic brain injury by suppressing STAT3 signaling in rats

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