MADR2 Is a Substrate of the TGFβ Receptor and Its Phosphorylation Is Required for Nuclear Accumulation and Signaling

Macı́as-Silva, Marina; Abdollah, Shirin; Hoodless, Pamela A.; Pirone, Rosa; Attisano, Liliana; Wrana, Jeffrey L.

doi:10.1016/s0092-8674(00)81817-6

Cited by 686 publications

(616 citation statements)

References 34 publications

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“…Smad6 inhibits ALK2 signaling through Smad1 but has no effect on signaling through Smads 2 and 3 that are downstream of ALK5 (Macias-Silva et al, 1996Imamura et al, 1997;Liu et al, 1997;Hata et al, 1998). Explants were infected with adenovirus coding for chicken Smad6 (Yamada et al, 1999) and GFP or adenovirus coding for GFP alone.…”

Section: Resultsmentioning

confidence: 99%

Transforming growth factor‐β stimulates epithelial–mesenchymal transformation in the proepicardium

Olivey

Mundell

Austin

et al. 2005

Developmental Dynamics

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The proepicardium (PE) migrates over the heart and forms the epicardium. A subset of these PE-derived cells undergoes epithelial-mesenchymal transformation (EMT) and gives rise to cardiac fibroblasts and components of the coronary vasculature. We report that transforming growth factor-␤ (TGF␤) 1 and TGF␤2 increase EMT in PE explants as measured by invasion into a collagen gel, loss of cytokeratin expression, and redistribution of ZO1. The type I TGF␤ receptors ALK2 and ALK5 are both expressed in the PE. However, only constitutively active (ca) ALK2 stimulates PE-derived epithelial cell activation, the first step in transformation, whereas caALK5 stimulates neither activation nor transformation in PE explants. Overexpression of Smad6, an inhibitor of ALK2 signaling, inhibits epithelial cell activation, whereas BMP7, a known ligand for ALK2, has no effect. These data demonstrate that TGF␤ stimulates transformation in the PE and suggest that ALK2 partially mediates this effect. Developmental Dynamics 235:50 -59, 2006.

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Section: Resultsmentioning

confidence: 99%

Transforming growth factor‐β stimulates epithelial–mesenchymal transformation in the proepicardium

Olivey

Mundell

Austin

et al. 2005

Developmental Dynamics

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“…The MH2 domain is important for homo-and heteromeric complex formation and for transcriptional activation and repression (Feng et al, 1998;Janknecht et al, 1998;Kawabata et al, 1998;Luo et al, 1999;Wotton et al, 1999). In addition, the MH2 domains of Smad2 and Smad3, but not Smad4, interact with type I receptors (Lo et al, 1998;MacõÂ as-Silva et al, 1996;Zhang et al, 1996). The MH1 domains of Smad3 and Smad4 have intrinsic binding activity to DNA sequences that contain 5'-AGAC-3' sequences, termed Smad-binding elements (SBEs) (Dennler et al, 1998;Jonk et al, 1998;Yingling et al, 1997;Zawel et al, 1998).…”

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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“…Both Smad4 family members play a central role in the downstream transduction of signals generated by TGF-b receptor family members. By forming heteromeric complexes with various pathway-restricted Smads, Smad4 participate in the activation of multiple signalling pathways initiated by TGF-b family members and may be directly involved in transcriptional activation of many downstream genes (Macias-Silva et al 1996;Kretzschmar et al 1997). As such, Smad4 plays a key role in the control of cell growth and differentiation.…”

Section: Introductionmentioning

confidence: 99%

Smad8B, a Smad8 splice variant lacking the SSXS site that inhibits Smad8‐mediated signalling

1999

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MADR2 Is a Substrate of the TGFβ Receptor and Its Phosphorylation Is Required for Nuclear Accumulation and Signaling

Cited by 686 publications

References 34 publications

Transforming growth factor‐β stimulates epithelial–mesenchymal transformation in the proepicardium

Transforming growth factor‐β stimulates epithelial–mesenchymal transformation in the proepicardium

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

Smad8B, a Smad8 splice variant lacking the SSXS site that inhibits Smad8‐mediated signalling

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