TβRI Phosphorylation of Smad2 on Ser465 and Ser467 Is Required for Smad2-Smad4 Complex Formation and Signaling

Abdollah, Shirin; Macı́as-Silva, Marina; Tsukazaki, Tomoo; Hayashi, Hidetoshi; Attisano, Liliana; Wrana, Jeffrey L.

doi:10.1074/jbc.272.44.27678

Cited by 453 publications

(344 citation statements)

References 38 publications

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“…They initiate cellular responses by binding to and activating speci®c receptors with intrinsic serine/ threonine kinase activity, whereby downstream e ectors, termed Smad proteins, are activated (Attisano and Wrana, 2000; ten Dijke et al, 2000). Smad2 and Smad3 are receptor-regulator Smads (R-Smads) which transiently interact with the activated TGF-b receptor and become phosphorylated at their extreme C-termini on two serine residues (Abdollah et al, 1997;Souchelnytskyi et al, 1997). Subsequently, activated Smad2 and Smad3 form heteromeric complexes with common-partner Smads (Co-Smads) (Lagna et al, 1996), e.g.…”

Section: Introductionmentioning

confidence: 99%

Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4

et al. 2000

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Smads, the intracellular e ectors of transforming growth factor-b (TGF-b) family members, are somatically mutated at high frequency in particular types of human cancers. Certain of these mutations a ect the Smad amino-terminal domain, which, in the case of Smad3 and Smad4, binds DNA. We investigated the functional consequences of four missense mutations in the Smad4 amino-terminal domain found in human tumors. The mutant proteins were found to have impaired abilities to bind DNA although they were fully capable of forming complexes with Smad3. All four Smad4 mutants showed decreased protein stability compared to wild-type Smad4. Two of the Smad4 mutants (G65V and P130S) were translocated to the nucleus and were capable of transactivating a Smad-dependent promoter in a liganddependent manner. In contrast, the L43S and R100T mutants were not translocated e ciently to the nucleus and consequently resulted in severely defective transcriptional responses to TGF-b. Moreover, we demonstrate here the critical importance of two basic residues in the b-hairpin loop of Smad3 or Smad4 for DNA binding, consistent with predictions from the Smad3 crystal structure. In addition, our results reveal that in the TGF-b-induced heteromeric signaling complex, loss of DNA binding of Smad4 can be compensated by Smad3, however, both Smad3 and Smad4 are needed for e cient DNA binding and signaling. In conclusion, mutations in the amino-terminal domain of Smad4, that are found in cancer, show loss of multiple functional properties which may contribute to tumorigenesis. Oncogene (2000) 19, 4396 ± 4404.

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Section: Introductionmentioning

confidence: 99%

Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4

et al. 2000

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“…These hemodynamic changes are followed by the activation of a number of cytokines (6,9,20,21,36,50), some of which have been directly linked to angiotensin II, such as monocyte chemotactic protein-1 (MCP-1) (20) and transforming growth factor-␤ (TGF-␤) (22), which appears to play a key role in the genesis of the ensuing fibrosis (32). TGF-␤ signaling is initiated after ligand binding to the TGF-␤ receptor (15,33), leading to phosphorylation of SMAD2 or SMAD3 (1,47,53). SMAD proteins represent a group of transcription factors involved in gene regulation downstream of the TGF-␤ receptor.…”

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confidence: 99%

AT_1A-mediated activation of kidney JNK1 and SMAD2 in obstructive uropathy: preservation of kidney tissue mass using candesartan

Davis

Padda

Truong³

et al. 2004

American Journal of Physiology-Renal Physiology

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-Hamad. AT1A-mediated activation of kidney JNK1 and SMAD2 in obstructive uropathy: preservation of kidney tissue mass using candesartan. Am J Physiol Renal Physiol 287: F474 -F480, 2004. First published May 4, 2004 10.1152/ajprenal.00452.2003.-Literature suggests the involvement of the renin-angiotensin system and transforming growth factor (TGF)-␤ in the renal injury that follows chronic ureteric obstruction. SMAD proteins and the JNK1 cascade are essential components of TGF-␤ signaling machinery, and recent data suggest cooperative interaction between JNK1 and SMAD proteins in TGF-␤-mediated gene expression. We used a rat model of chronic unilateral ureteric obstruction to study the effects of candesartan, an AT1A-receptor blocker, on tissue morphology and the activities of JNK1 and SMAD2 protein in the kidney. Ureteric obstruction for 28 days leads to interstitial fibrosis, tubule atrophy, and marked activation of SMAD2 and JNK1, without significant change in p38 kinase or ERK. Candesartan treatment, however, attenuated the chronic tubulointerstitial injury in obstructed kidneys and was associated with significant preservation of kidney tissue mass. Furthermore, treatment with candesartan diminished JNK1 activity and downregulated SMAD2 protein and activity in obstructed kidneys. In conclusion, obstructed kidneys showed chronic tubulointerstitial injury, which was associated with JNK1 and SMAD2 activation. The renoprotective effects afforded by AT1A-receptor blockade in obstructive uropathy are consistent with attenuation of JNK1-and SMAD2-mediated renal injury.

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“…Like Stats, they are mainly in the cytoplasm in their inactivated forms and upon TGFβ stimulation, phosphorylated RSmads form a complex with Smad4 and accumulate in the nucleus to regulate transcription. Smads are directly phosphorylated on serine residues by the TGFβ receptors, thus providing a direct link between cytokine binding and gene regulation [44][45][46][47][48].…”

Section: −2 Nuclear Translocation Of Smad Proteinsmentioning

confidence: 99%

Cytokine-induced nuclear translocation of signaling proteins and their analysis using the inducible translocation trap system

Fleur

Fujii

2008

Cytokine

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Binding of cytokines to their specific receptors induces activation of signal transduction pathways, many of which involve nuclear translocation of signaling proteins. In this review, an overview of cytokine-induced nuclear translocation of signaling proteins is provided. In addition, inducible translocation trap (ITT), a novel reporter-based system to detect nuclear translocation, and its application for identification of nuclear translocating proteins are elaborated. Finally, analysis of "nuclear translocatome", the entire set of proteins that translocate into or out of the nucleus in response to extracellular stimuli, by ITT is discussed.

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TβRI Phosphorylation of Smad2 on Ser465 and Ser467 Is Required for Smad2-Smad4 Complex Formation and Signaling

Cited by 453 publications

References 38 publications

Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4

Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4

AT_1A-mediated activation of kidney JNK1 and SMAD2 in obstructive uropathy: preservation of kidney tissue mass using candesartan

Cytokine-induced nuclear translocation of signaling proteins and their analysis using the inducible translocation trap system

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