APC and Smad7 link TGFβ type I receptors to the microtubule system to promote cell migration

Ekman, Martin; Mu, Yabing; Lee, So Young; Edlund, Sofia; Kozakai, Takaharu; Thakur, Noopur; Hoanh, Tran; Jiang, Qian; Groeden, Joanna; Heldin, Carl‐Henrik; Landström, Maréne

doi:10.1091/mbc.e10-12-1000

Cited by 34 publications

(33 citation statements)

References 56 publications

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“…Treatment of PC-3U cells with the p38-inhibitor SB203580, resulted in an inhibition of TGFβ-induced phosphorylation of GSK-3β on Ser9 (Fig. 3D), suggesting that p38 causes inactivation of GSK-3β, consistent with previous observations 36 , 37 …”

Section: Resultssupporting

confidence: 91%

TGFβ-induced invasion of prostate cancer cells is promoted by c-Jun-dependent transcriptional activation of Snail1

et al. 2014

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High levels of transforming growth factor-β (TGFβ) correlate with poor prognosis for patients with prostate cancer and other cancers. TGFβ is a multifunctional cytokine and crucial regulator of cell fate, such as epithelial to mesenchymal transition (EMT), which is implicated in cancer invasion and progression. TGFβ conveys its signals upon binding to type I and type II serine/threonine kinase receptors (TβRI/II); phosphorylation of Smad2 and Smad3 promotes their association with Smad4, which regulates expression of targets genes, such as Smad7, p21, and c-Jun. TGFβ also activates the ubiquitin ligase tumor necrosis factor receptor-associated factor 6 (TRAF6), which associates with TβRI and activates the p38 mitogen-activated protein kinase (MAPK) pathway. Snail1 is a key transcription factor, induced by TGFβ that promotes migration and invasion of cancer cells. In this study, we have identified a novel binding site for c-Jun in the promoter of the Snail1 gene and report that the activation of the TGFβ–TRAF6–p38 MAPK pathway promotes both c-Jun expression and its activation via p38α-dependent phosphorylation of c-Jun at Ser63. The TRAF6-dependent activation of p38 also leads to increased stability of c-Jun, due to p38-dependent inactivation of glycogen synthase kinase (GSK) 3β by phosphorylation at Ser9. Thus, our findings elucidate a novel role for the p38 MAPK pathway in stimulated cells, leading to activation of c-Jun and its binding to the promoter of Snail1, thereby triggering motility and invasiveness of aggressive human prostate cancer cells.

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Section: Resultssupporting

confidence: 91%

TGFβ-induced invasion of prostate cancer cells is promoted by c-Jun-dependent transcriptional activation of Snail1

et al. 2014

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“…The results showed that miR-497 was significantly downregulated in breast cancer tissues compared with normal tissues, which was consistent with the Dan Li's findings (Li et al, 2011). As an inhibitor of TGF-b signaling, SMAD7 was overexpressed in numerous cancers and its abundance was positively associated with the cancer malignancy (Ekman et al, 2012;Stolfi et al, 2013). Nevertheless, in breast cancer, studies revealed that SMAD7 could exert both anti-and protumor effects.…”

Section: )supporting

confidence: 84%

microRNA-497 Modulates Breast Cancer Cell Proliferation, Invasion, and Survival by Targeting SMAD7

Liu

Zhou

Shi

et al. 2016

DNA and Cell Biology

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As an inhibitor of TGF-β signaling, SMAD7 was reported to play dual roles in breast cancer development and progression. It inhibited the cancer metastasis by blocking epithelial-mesenchymal transition, however, litter studies focused on its role in other cancer processes. In this study, miR-497 expression was found inversely correlated with SMAD7 expression in breast cancer tissues. Bioinformatics analyses defined a potential miR-497 response element within 3' untranslated region of SMAD7 that was validated in reporter gene experiments. Enforced miR-497 expression, accompanied with SMAD7 reduction, suppressed MDA-MB-231 and MCF-7 breast cancer cell growth by MTT and invasion assay, and, induced the S phase arrest detected by flow cytometry. Furthermore, upregulated miR-497 expression by mimics treatment significantly suppressed the tumor growth in the orthotopic nude mouse models. Finally, high expression of miR-497 conferred a better prognosis, indicated by Kaplan-Meier test, especially in HER2 overexpression and triple-negative breast cancer (TNBC). Taken together, our results identified the proliferation promoting role of SMAD7 in breast cancer and therefore established the regulations of SMAD7 in breast cancer by miR-497 through a posttranscriptional mechanism. Moreover, miR-497 might be deemed as a novel potential therapeutic target for the HER2 positive and TNBC in future.

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“…In non-epithelial or not polarized epithelial cells, TGFβ receptors are distributed more randomly, though immunofluorescence staining revealed high concentration of the receptors in membrane ruffles and in the leading edge of migrating cells [19,20]; however, it is not clear whether these receptors were exposed on the cell surface. It would be interesting to investigate if front-rear polarization of the cells affects the distribution of the TGFβ receptors in the plasma membrane similar to the apical-basolateral one.…”

Section: Distribution Of Tgfβ Receptors In the Plasma Membranementioning

confidence: 96%

Intracellular trafficking of transforming growth factor β receptors

Yakymovych

Heldin

2018

ABBS

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Transforming growth factor β (TGFβ) family members signal via heterotetrameric complexes of type I (TβRI) and type II (TβRII) dual specificity kinase receptors. The availability of the receptors on the cell surface is controlled by several mechanisms. Newly synthesized TβRI and TβRII are delivered from the Golgi apparatus to the cell surface via separate routes. On the cell surface, TGFβ receptors are distributed between different microdomains of the plasma membrane and can be internalized via clathrin-and caveolae-mediated endocytic mechanisms. Although receptor endocytosis is not essential for TGFβ signaling, localization of the activated receptor complexes on the early endosomes promotes TGFβ-induced Smad activation. Caveolae-mediated endocytosis, which is widely regarded as a mechanism that facilitates the degradation of TGFβ receptors, has been shown to be required for TGFβ signaling via non-Smad pathways. The importance of proper control of TGFβ receptor intracellular trafficking is emphasized by clinical data, as mislocalization of receptors has been described in connection with several human diseases. Thus, control of intracellular trafficking of the TGFβ receptors together with the regulation of their expression, posttranslational modifications and down-regulation, ensure proper regulation of TGFβ signaling.

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APC and Smad7 link TGFβ type I receptors to the microtubule system to promote cell migration

Abstract: A novel function for Smad7 is demonstrated in the establishment of cell polarity during cell migration in certain cell types. TGFβ type I receptors, Smad7, active p38, and APC are localized in the leading edge of polarized, migrating cells.

Cited by 34 publications

References 56 publications

TGFβ-induced invasion of prostate cancer cells is promoted by c-Jun-dependent transcriptional activation of Snail1

TGFβ-induced invasion of prostate cancer cells is promoted by c-Jun-dependent transcriptional activation of Snail1

microRNA-497 Modulates Breast Cancer Cell Proliferation, Invasion, and Survival by Targeting SMAD7

Intracellular trafficking of transforming growth factor β receptors

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APC and Smad7 link TGFβ type I receptors to the microtubule system to promote cell migration

Abstract: A novel function for Smad7 is demonstrated in the establishment of cell polarity during cell migration in certain cell types. TGFβ type I receptors, Smad7, active p38, and APC are localized in the leading edge of polarized, migrating cells.

Cited by 34 publications

References 56 publications

TGFβ-induced invasion of prostate cancer cells is promoted by c-Jun-dependent transcriptional activation of Snail1

TGFβ-induced invasion of prostate cancer cells is promoted by c-Jun-dependent transcriptional activation of Snail1

microRNA-497 Modulates Breast Cancer Cell Proliferation, Invasion, and Survival by Targeting SMAD7

Intracellular trafficking of transforming growth factor &beta; receptors

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Intracellular trafficking of transforming growth factor β receptors