Identification of Tyrosine-Phosphorylated Proteins Upregulated during Epithelial–Mesenchymal Transition Induced with TGF-β

Okayama, Akira; Miyagi, Yohei; Oshita, Fumihiro; Ito, Hiroyuki; Nakayama, Haruhiko; Nishi, Mayuko; Kurata, Yoichi; Kimura, Yayoi; Ryo, Akihide; Hirano, Hisashi

doi:10.1021/acs.jproteome.5b00082

Cited by 20 publications

(22 citation statements)

References 45 publications

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“…We found that, under TGF-b treatment for extended periods of time, we occasionally observed a doublet signal for TNS1 ( Figure 4B). The appearance of a second, higher apparent molecular weight band could potentially represent electrophoretic mobility shift due to increased phosphorylation, given the presence of abundant serine/threonine and tyrosine phosphorylation sites on TNS1, including a report of increased phosphorylation at Y1404 in response to TGF-b (9,34). Unexpectedly, we observed that knockdown of TNS1 using any of these siRNA constructs resulted in loss of TGFb-induced myofibroblast differentiation, as determined by ACTA2 expression ( Figure 4B).…”

Section: Tns1 Is Essential For Myofibroblast Differentiationmentioning

confidence: 75%

Tensin 1 Is Essential for Myofibroblast Differentiation and Extracellular Matrix Formation

Bernau¹,

Torr²,

Evans

et al. 2017

Am J Respir Cell Mol Biol

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Myofibroblasts, the primary effector cells that mediate matrix remodeling during pulmonary fibrosis, rapidly assemble an extracellular fibronectin matrix. Tensin (TNS) 1 is a key component of specialized cellular adhesions (fibrillar adhesions) that bind to extracellular fibronectin fibrils. We hypothesized that TNS1 may play a role in modulating myofibroblast-mediated matrix formation. We found that TNS1 expression is increased in fibroblastic foci from lungs with idiopathic pulmonary fibrosis. Transforming growth factor (TGF)-β profoundly up-regulates TNS1 expression with kinetics that parallel the expression of the myofibroblast marker, smooth muscle α-actin. TGF-β-induced TNS1 expression is dependent on signaling through the TGF-β receptor 1 and is Rho coiled-coiled kinase/actin/megakaryoblastic leukemia-1/serum response factor dependent. Small interfering RNA-mediated knockdown of TNS1 disrupted TGF-β-induced myofibroblast differentiation, without affecting TGF-β/Smad signaling. In contrast, loss of TNS1 resulted in disruption of focal adhesion kinase phosphorylation, focal adhesion formation, and actin stress fiber development. Finally, TNS1 was essential for the formation of fibrillar adhesions and the assembly of nascent fibronectin and collagen matrix in myofibroblasts. In summary, our data show that TNS1 is a novel megakaryoblastic leukemia-1-dependent gene that is induced during pulmonary fibrosis. TNS1 plays an essential role in TGF-β-induced myofibroblast differentiation and myofibroblast-mediated formation of extracellular fibronectin and collagen matrix. Targeted disruption of TNS1 and associated signaling may provide an avenue to inhibit tissue fibrosis.

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Section: Tns1 Is Essential For Myofibroblast Differentiationmentioning

confidence: 75%

Tensin 1 Is Essential for Myofibroblast Differentiation and Extracellular Matrix Formation

Bernau¹,

Torr²,

Evans

et al. 2017

Am J Respir Cell Mol Biol

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“…The epithelial- mesenchymal transition (EMT) was an unique process for the phenotypic changes of tumor cells characterized by a transition from polarized rigid epithelial cells to migrant mesenchymal cells, thus conferring the ability of tumor invasion and metastasis 52 . EMT could suppress tubulin tyrosine ligaseand promote microtubule stability 53 , resulting in tubulin detyrosination and the formation of microtentacles for supporting endothelial cell attachment 54 .…”

Section: Resultsmentioning

confidence: 99%

Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

Liu

et al. 2017

Sci Rep

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We have synthesized a series of new β-lactam-azide derivatives as orally active anti-tumor agents by targeting tubulin colchicine binding site and examined their structure activity relationship (SAR). Among them, compound 28 exhibited the most potent antiproliferative activity against MGC-803 cells with an IC50 value of 0.106 μM by induction of G2/M arrest and apoptosis and inhibition of the epithelial to mesenchymal transition. 28 acted as a novel inhibitor of tubulin polymerization by its binding to the colchicine site. SAR analysis revealed that a hydrogen atom at the C-3 position of the β-lactam was required for the potent antiproliferative activity of β-lactam-azide derivatives. Oral administration of compound 28 also effectively inhibited MGC-803 xenograft tumor growth in vivo in nude mice without causing significant loss of body weight. These results suggested that compound 28 is a promising orally active anticancer agent with potential for development of further clinical applications.

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“…Many of these phosphoproteins have known functional properties that are linked to the differentiation of epithelial cells or the fibrotic response, including ECM proteins [ 119 ]. A more focused screen has analyzed only the tyrosine-phosphorylated proteins in lung adenocarcinoma cells responding to TGFβ and undergoing EMT [ 120 ]. Both growth factor receptors (e.g., c-Met) and regulatory cytoplasmic proteins (e.g., tensin) were identified in this screen on the basis of having their phospho-tyrosine content increased at specific tyrosine residues.…”

Section: Regulatory Mechanisms That Control Tgfβ-induced Emtmentioning

confidence: 99%

Mechanisms of TGFβ-Induced Epithelial–Mesenchymal Transition

Moustakas

Heldin

2016

JCM

223

162

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Transitory phenotypic changes such as the epithelial–mesenchymal transition (EMT) help embryonic cells to generate migratory descendants that populate new sites and establish the distinct tissues in the developing embryo. The mesenchymal descendants of diverse epithelia also participate in the wound healing response of adult tissues, and facilitate the progression of cancer. EMT can be induced by several extracellular cues in the microenvironment of a given epithelial tissue. One such cue, transforming growth factor β (TGFβ), prominently induces EMT via a group of specific transcription factors. The potency of TGFβ is partly based on its ability to perform two parallel molecular functions, i.e. to induce the expression of growth factors, cytokines and chemokines, which sequentially and in a complementary manner help to establish and maintain the EMT, and to mediate signaling crosstalk with other developmental signaling pathways, thus promoting changes in cell differentiation. The molecules that are activated by TGFβ signaling or act as cooperating partners of this pathway are impossible to exhaust within a single coherent and contemporary report. Here, we present selected examples to illustrate the key principles of the circuits that control EMT under the influence of TGFβ.

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Identification of Tyrosine-Phosphorylated Proteins Upregulated during Epithelial–Mesenchymal Transition Induced with TGF-β

Cited by 20 publications

References 45 publications

Tensin 1 Is Essential for Myofibroblast Differentiation and Extracellular Matrix Formation

Tensin 1 Is Essential for Myofibroblast Differentiation and Extracellular Matrix Formation

Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

Mechanisms of TGFβ-Induced Epithelial–Mesenchymal Transition

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