SnoN Is a Cell Type-specific Mediator of Transforming Growth Factor-β Responses

Sarker, Krishna Pada; Wilson, Sylvia M.; Bonni, Shirin

doi:10.1074/jbc.m409367200

Cited by 67 publications

(103 citation statements)

References 54 publications

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“…51 More important, many human cancer cell lines that express high levels of SnoN are refractory to TGF-␤-induced growth arrest. 52 Altogether, these data suggest that PTP1B deficiency affects the early triggers of the regenerative response after PH and mediates gene expression related to the termination of this process. Therefore, the molecular mechanism by which PTP1B modulates SnoN expression deserves further investigation.…”

Section: Discussionmentioning

confidence: 82%

Protein Tyrosine Phosphatase 1B (PTP1B) Deficiency Accelerates Hepatic Regeneration in Mice

Revuelta-Cervantes

Mayoral

Miranda

et al. 2011

The American Journal of Pathology

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Protein tyrosine phosphatase 1B (PTP1B) is a key regulator of metabolism and cell growth by its ability to dephosphorylate tyrosine kinase receptors and modulate the intensity of their signaling cascades. Because liver regeneration involves tyrosine phosphorylation-mediated signaling, we investigated the role of PTP1B in this process by performing partial hepatectomy in wild-type (PTP1B ؉/؉ ) and PTP1B-deficient (PTP1B ؊/؊ ) mice. The expression of PCNA and cyclins D1 and E (cell proliferation markers) was enhanced in PTP1B ؊/؊ regenerating livers, in parallel with 5=-bromo-2=-deoxyuridine incorporation. Phosphorylation of JNK1/2 and STAT3, early triggers of hepatic regeneration in response to TNF-␣ and IL-6, was accelerated in PTP1B ؊/؊ mice compared with PTP1B ؉/؉ mice. These phosphorylations were increased in PTP1B ؊/؊ hepatocytes or by silencing PTP1B in wild-type cells and decreased further after the addition of recombinant PTP1B. Enhanced EGFand HGF receptor-mediated signaling was observed in regenerating livers lacking PTP1B and in EGF-or HGF-stimulated PTP1B ؊/؊ hepatocytes. Moreover, PTP1B ؊/؊ mice displayed a more rapid increase in intrahepatic lipid accumulation than PTP1B ؉/؉ control mice. Late responses to partial hepatectomy revealed additional divergences because stress-mediated signaling was attenuated at 24 to 96 hours in PTP1B ؊/؊ mice compared with PTP1B ؉/؉ mice. Finally, PTP1B deficiency also improves hepatic regeneration in mice fed a high-fat diet. These results suggest that pharmacological inhibition of PTP1B would improve liver regeneration in patients with acute or chronic liver injury.

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Section: Discussionmentioning

confidence: 82%

Protein Tyrosine Phosphatase 1B (PTP1B) Deficiency Accelerates Hepatic Regeneration in Mice

Revuelta-Cervantes

Mayoral

Miranda

et al. 2011

The American Journal of Pathology

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“…Fold-induction of ADAM12 by TGF␤1 was quantified by densitometry and ImageJ; the data represent the means from three different determinations Ϯ S.E. mediator of transcription (50). Indeed, a microarray analysis of human lung cancer A549 cells demonstrated that a large set of genes is down-regulated in cells lacking SnoN, suggesting that SnoN may function as a transcriptional activator, in addition to acting as a transcriptional repressor of the Smad proteins (43).…”

Section: Discussionmentioning

confidence: 99%

The Role of SnoN in Transforming Growth Factor β1-induced Expression of Metalloprotease-Disintegrin ADAM12

Solomon

Muggy

et al. 2010

Journal of Biological Chemistry

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Increased expression of metalloprotease-disintegrin ADAM12 is a hallmark of several pathological conditions, including cancer, cardiovascular disease, and certain inflammatory diseases of the central nervous system or the muscoskeletal system. We show that transforming growth factor ␤1 (TGF␤1) is a potent inducer of ADAM12 mRNA and protein in mouse fibroblasts and in mouse and human mammary epithelial cells. Induction of ADAM12 is detected within 2 h of treatment with TGF␤1, is Smad2/Smad3-dependent, and is a result of derepression of the ADAM12, a member of the metalloprotease-disintegrin family of proteins, has been implicated in the progression of cancer, cardiovascular disease, osteoarthritis, and neurological disorders (1). The ADAM12 gene is frequently mutated in human breast cancers (2, 3), and cancer-associated mutations cause mislocalization of the ADAM12 protein in cells and alter its function (4). Missense single nuclear polymorphism in the ADAM12 gene shows strong association with osteoarthritis (5, 6). In addition to changes in its amino acid sequence, expression levels of ADAM12 are significantly increased in many pathological states. For example, ADAM12 expression levels are 20 -30-fold higher in human breast tumors than in normal mammary epithelium (7-12). ADAM12 expression is also markedly up-regulated in cancers of the liver, lung, stomach, colon, prostate, bladder, and in glioblastoma (13-18). Increased ADAM12 expression levels are found in the cardiac tissue of patients with hypertrophic obstructive cardiomyopathy (19) and in mice with angiotensin II-induced hypertension and cardiac hypertrophy (20,21). During inflammatory responses and aseptic osteolysis associated with loosened hip replacement implants, ADAM12 is up-regulated in the interface tissue around loosening implants (22). In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, ADAM12 level is markedly increased in the T cells that infiltrate spinal cords (23).The mechanisms regulating ADAM12 expression, in particular those that may be responsible for altered levels of ADAM12 in various pathological states, are poorly understood. Previous studies employing hepatic stellate cells, a mesenchymal cell type in hepatic parenchyma, have indicated that ADAM12 expression is induced by transforming growth factor ␤ (TGF␤) 2 (13, 24). The TGF␤ signaling pathway is initiated when one of the family members, e.g. TGF␤1, -␤2, or -␤3, binds to a complex of TGF␤ type I and type II serine/threonine kinase receptors (T␤RI and T␤RII, respectively) and induces phosphorylation and activation of T␤RI by T␤RII. T␤RI then phosphorylates receptor Smads (R-Smads), Smad2 and Smad3. Phosphorylated Smad2/3 associate with the common partner Smad4 and translocate to the nucleus, where they regulate transcription of target genes (25,26). In addition, receptor activation in certain cell types leads to Smad-independent responses via the activation of mitogen-activated protein kinases (MAPKs), phosphoinositide 3-kinase, and Rho family memb...

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“…14,69,70,71 Smurf2 RNAi vectors encoding Smurf2 hairpin RNAs targeting one of two distinct regions in Smurf2 (5′-GGGCCAAATGACAATGATACA-3′ (Smurf2i-1) and 5′-GGGAAGT CAATTACCTTGGAT-3′ (Smurf2i-2)) and enhanced green fluorescent protein (EGFP) under the control of the U6 and CMV promoters were cloned as previously described. 72,73 RNAi-resistant Smurf2 plasmids Smurf2(r1) and Smurf2(r2) were generated by mutating the Smurf2 cDNA corresponding to the RNAi-1 and RNAi-2 target regions. 70,73 The plasmids were confirmed by DNA sequence analyses (University of Calgary Core Sequencing Facility, Calgary, AB, Canada).…”

Section: Methodsmentioning

confidence: 99%

“…72,73 RNAi-resistant Smurf2 plasmids Smurf2(r1) and Smurf2(r2) were generated by mutating the Smurf2 cDNA corresponding to the RNAi-1 and RNAi-2 target regions. 70,73 The plasmids were confirmed by DNA sequence analyses (University of Calgary Core Sequencing Facility, Calgary, AB, Canada). The Smad2 and Smad3 RNAi vectors 74,75 and the FLAG/SENP1 and FLAG/SENP2 expression plasmids were kind gifts from Dr. Azad Bonni (Washington University School of Medicine St. Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

“…For in vivo sumoylation assays, cells were lysed in TNTE (50 mM Tris, 150 mM NaCl, and 1 mM EDTA) buffer containing 0.5% Triton X-100 along with protease and phosphatase inhibitors, and 0.1% SDS. 69,73,76 In addition, 20 mM NEM isopeptidase inhibitor was included in the lysis buffer where indicated. 45,65 Cell extracts were collected in 1.75 ml Eppendorf tubes and centrifuged at 14 000 × g for 10 min at 4°C.…”

Section: Methodsmentioning

confidence: 99%

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The ubiquitin ligase Smurf2 suppresses TGFβ-induced epithelial–mesenchymal transition in a sumoylation-regulated manner

Karve

Dadakhujaev

et al. 2015

Cell Death Differ

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Epithelial-mesenchymal transition (EMT) is a fundamental cellular process in epithelial tissue development, and can be reactivated in cancer contributing to tumor invasiveness and metastasis. The cytokine transforming growth factor-β (TGFβ) is a key inducer of EMT, but the mechanisms that regulate TGFβ-induced EMT remain incompletely understood. Here, we report that knockdown of the ubiquitin ligase Smurf2 promotes the ability of TGFβ to induce EMT in a three-dimensional cell culture model of NMuMG mammary epithelial cells. In other studies, we identify Smurf2 as a target of the small ubiquitin like modifier (SUMO) pathway. We find that the SUMO-E2 conjugating enzyme Ubc9 and the SUMO E3 ligase PIAS3 associate with Smurf2 and promote its sumoylation at the distinct sites of Lysines 26 and 369. The sumoylation of Smurf2 enhances its ability to induce the degradation of the TGFβ receptor and thereby suppresses EMT in NMuMG cells. Collectively, our data reveal that Smurf2 acts in a sumoylationregulated manner to suppress TGFβ-induced EMT. These findings have significant implications for our understanding of epithelial tissue development and cancer. Cell Death and Differentiation (2016) 23, 876-888; doi:10.1038/cdd.2015; published online 18 December 2015Epithelial-mesenchymal transition (EMT) is an essential process in epithelial tissue morphogenesis in the developing organism and contributes to postnatal events including mammary postnatal gland development as well as wound healing.1,2 Importantly, EMT can be reactivated during cancer and may contribute to tumor invasiveness.3 Epithelial cells undergoing EMT change phenotypically from cuboidal to fibroblastic morphology, lose epithelial markers including E-cadherin, gain mesenchymal markers, and display increased cell motility and invasiveness. 4,5 The secreted factor transforming growth factor-β (TGFβ) has emerged as a potent inducer of EMT with key roles in development and cancer.6 Thus, there has been interest in the mechanisms that mediate TGFβ-induced EMT.Smurf2 (Smad (Sma and mad) ubiquitination regulatory factor-2) is a HECT (for homology to E6 carboxy terminus domain)-containing E3 ubiquitin ligase that specifies substrates for ubiquitination and degradation by the proteasome.7,8 Smurf2 regulates key biological processes during development and homeostasis including cell polarity, cell cycle, and senescence in an E3 ligase-dependent or -independent manner.9-15 The biological functions of Smurf2 occur via regulation of signaling pathways including the TGFβ-Smad signaling pathway. [16][17][18][19][20][21][22][23] However, the role of Smurf2 in TGFβ-induced EMT has remained to be determined.Sumoylation refers to the covalent attachment of the small ubiquitin-like modifier (SUMO), to protein substrates by the SUMO pathway.24 SUMO is linked to its substrates by an iso-peptide bond between C-terminal carboxyl group of SUMO and ε-amino group of a lysine residue in the substrate. The SUMO E2 conjugating enzyme Ubc9, the second enzyme of a three-step catalytic cascade...

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SnoN Is a Cell Type-specific Mediator of Transforming Growth Factor-β Responses

Cited by 67 publications

References 54 publications

Protein Tyrosine Phosphatase 1B (PTP1B) Deficiency Accelerates Hepatic Regeneration in Mice

Protein Tyrosine Phosphatase 1B (PTP1B) Deficiency Accelerates Hepatic Regeneration in Mice

The Role of SnoN in Transforming Growth Factor β1-induced Expression of Metalloprotease-Disintegrin ADAM12

The ubiquitin ligase Smurf2 suppresses TGFβ-induced epithelial–mesenchymal transition in a sumoylation-regulated manner

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