Smad7 Inhibits Transforming Growth Factor-β Family Type I Receptors through Two Distinct Modes of Interaction

Kamiya, Yuto; Miyazono, Kohei; Miyazawa, Keiji

doi:10.1074/jbc.m110.166140

Cited by 57 publications

(57 citation statements)

References 31 publications

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“…Moreover, BMP signalling induces the transcriptional activation of target genes encoding inhibitory Smad proteins, Smad6 and Smad7. Smad6/7 function at several points in the pathway, namely to inhibit R-Smad phosphorylation, and Smad complex formation and its transcriptional activity [33][34][35]. This mechanism is likely not operational in EOC spheroid cells because Smad6/7 mRNA expression does not change in EOC spheroids, and Smad6 protein levels are not consistent among EOC cells and spheroids generated from patient samples (data not shown).…”

Section: Discussionmentioning

confidence: 65%

BMP signalling controls the malignant potential of ascites-derived human epithelial ovarian cancer spheroids via AKT kinase activation

Peart

Correa

Valdes³

et al. 2012

Clin Exp Metastasis

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Epithelial ovarian cancer (EOC) cells have the ability to form multi-cellular aggregates in malignant ascites which dramatically alters cell signalling, survival, and metastatic potential. Herein, we demonstrate that patient ascites-derived EOC cells down-regulate endogenous bone morphogenetic protein (BMP) signalling by decreasing BMP ligand expression when grown in suspension culture to form spheroids. Enforced BMP signalling in these cells via constitutively-active BMP type I ALK3(QD) receptor expression causes the formation of smaller, more loosely-aggregated spheroids. Additionally, ALK3(QD)-expressing spheroids have an increased rate of adhesion and dispersion upon reattachment to substratum. Inhibition of endogenous BMP signalling using recombinant Noggin or small molecule inhibitor LDN-193189, on the other hand, opposed these phenotypic changes. To identify potential targets that impact the phenotype of EOC spheroids due to activated BMP signalling, we performed genome-wide expression analyses using Affymetrix arrays. Using the online Connectivity Map resource, the BMP signalling gene expression signature revealed that the AKT pathway is induced by activated BMP signalling in EOC cells; this finding was further validated by phospho-AKT immuno-blotting. In fact, treatment of EOC spheroids with an AKT inhibitor, Akti-1/2, reduced BMP-stimulated cell dispersion during reattachment as compared to controls. Thus, we have identified AKT as being one important downstream component of activated BMP signalling on EOC spheroid pathobiology, which may have important implications on the metastatic potential of this malignancy.

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Section: Discussionmentioning

confidence: 65%

BMP signalling controls the malignant potential of ascites-derived human epithelial ovarian cancer spheroids via AKT kinase activation

Peart

Correa

Valdes³

et al. 2012

Clin Exp Metastasis

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“…As mentioned above, Smad7 is induced by TGFβ stimulation and then acts in a negative feedback mechanism, by competing with R-Smads for receptor binding thus inhibiting their phosphorylation Kamiya et al 2010;Nakao et al 1997), by recruiting ubiquitin ligases to the receptors thus promoting their ubiquitination and proteasomal degradation Kavsak et al 2000), by recruiting phosphatases to the receptors thus promoting their dephosphorylation and deactivation and by interfering with the binding of Smad complexes to DNA ). However, Smad7 also has other functions, e.g., as an adaptor to facilitate the activation of p38 MAP kinase (Landström, this issue) and as a transcriptional regulator in the nucleus (Miyake et al 2010).…”

Section: Negative Feedback Control Of Smad Signalingmentioning

confidence: 96%

Role of Smads in TGFβ signaling

2011

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Transforming growth factor-β (TGFβ) is the prototype for a large family of pleiotropic factors that signal via heterotetrameric complexes of type I and type II serine/threonine kinase receptors. Important intracellular mediators of TGFβ signaling are members of the Smad family. Smad2 and 3 are activated by C-terminal receptor-mediated phosphorylation, whereafter they form complexes with Smad4 and are translocated to the nucleus where they, in cooperation with other transcription factors, co-activators and co-repressors, regulate the transcription of specific genes. Smads have key roles in exerting TGFβ-induced programs leading to cell growth arrest and epithelial-mesenchymal transition. The activity and stability of Smad molecules are carefully regulated by a plethora of post-translational modifications, including phosphorylation, ubiquitination, sumoylation, acetylation and poly(ADP)-ribosylation. The Smad function has been shown to be perturbed in certain diseases such as cancer.

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“…As Smad7 associates with TAK1, a tempting speculation is that Smad7 also plays an important role in cell migration. The observation that Smad7 harbors, in its C-terminus, two specific motifs by which it can be recruited to the activated TβR complex to prevent the activation of the R-Smads suggests a dual function of Smad7: to inhibit TGFβ-Smad signaling and to facilitate TGFβ-induced activation of the p38 and JNK MAPK pathways (Kamiya et al 2010;Yan and Chen 2011 Fig. 2 TGFβ, environmental stress, and inflammatory cytokines regulate TGFβ-associated kinase 1 (TAK1) activity.…”

Section: Smad7 Acts As An Adaptor Protein To Cause Activation Of Non-mentioning

confidence: 99%

Non-Smad signaling pathways

2011

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Transforming growth factor-beta (TGFβ) is a key regulator of cell fate during embryogenesis and has also emerged as a potent driver of the epithelial-mesenchymal transition during tumor progression. TGFβ signals are transduced by transmembrane type I and type II serine/threonine kinase receptors (TβRI and TβRII, respectively). The activated TβR complex phosphorylates Smad2 and Smad3, converting them into transcriptional regulators that complex with Smad4. TGFβ also uses non-Smad signaling pathways such as the p38 and Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways to convey its signals. Ubiquitin ligase tumor necrosis factor (TNF)-receptor-associated factor 6 (TRAF6) and TGFβ-associated kinase 1 (TAK1) have recently been shown to be crucial for the activation of the p38 and JNK MAPK pathways. Other TGFβ-induced non-Smad signaling pathways include the phosphoinositide 3-kinase-Akt-mTOR pathway, the small GTPases Rho, Rac, and Cdc42, and the Ras-Erk-MAPK pathway. Signals induced by TGFβ are tightly regulated and specified by post-translational modifications of the signaling components, since they dictate the subcellular localization, activity, and duration of the signal. In this review, we discuss recent findings in the field of TGFβ-induced responses by non-Smad signaling pathways.

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Smad7 Inhibits Transforming Growth Factor-β Family Type I Receptors through Two Distinct Modes of Interaction

Cited by 57 publications

References 31 publications

BMP signalling controls the malignant potential of ascites-derived human epithelial ovarian cancer spheroids via AKT kinase activation

BMP signalling controls the malignant potential of ascites-derived human epithelial ovarian cancer spheroids via AKT kinase activation

Role of Smads in TGFβ signaling

Non-Smad signaling pathways

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