Microtubule Binding to Smads May Regulate TGFβ Activity

Dong, Chunming; Li, Zhi‐Ru; Alvarez, René; Feng, Xin; Goldschmidt‐Clermont, Pascal J.

doi:10.1016/s1097-2765(00)80400-1

Cited by 258 publications

(243 citation statements)

References 14 publications

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“…Smad activity is modulated by a number of cofactors, such as embryonic liver fodrin (ELF), SARA, Filamin and microtubules, each of which functionally interacts with multiple other signal transduction pathways (Tsukazaki et al, 1998;Dong et al, 2000;Tang Y et al, 2003). Adaptor proteins, such as SARA and ELF, play critical roles in the proper control of Smad access to the receptors for activation at the cell membrane, thus facilitating TGF-b functions such as growth, differentiation and cell fate specification.…”

Section: Introductionmentioning

confidence: 99%

Critical interactions between TGF-β signaling/ELF, and E-cadherin/β-catenin mediated tumor suppression

Katuri

Tang

et al. 2006

Oncogene

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Inactivation of the transforming growth factor-b (TGF-b) pathway occurs often in malignancies of the gastrointestinal (GI) system. However, only a fraction of sporadic GI tumors exhibit inactivating mutations in early stages of cancer formation, suggesting that other mechanisms play a critical role in the inactivation of this pathway. Here, we show a wide range of GI tumors, including those of the stomach, liver and colon in elf þ /À and elf þ /À /Smad4 þ /À mutant mice. We found that embryonic liver fodrin (ELF), a b-Spectrin originally identified in endodermal stem/ progenitor cells committed to foregut lineage, possesses potent antioncogenic activity and is frequently inactivated in GI cancers. Specifically, E-cadherin accumulation at cell-cell contacts and E-cadherin-b-catenin-dependent epithelial cell-cell adhesion is disrupted in elf þ /À / Smad4 þ /À mutant gastric epithelial cells, and could be rescued by ectopic expression of full-length elf, but not Smad3 or Smad4. Subcellular fractionation revealed that E-cadherin is expressed mainly at the cell membrane after TGF-b stimulation. In contrast, elf þ /À /Smad4 þ /À mutant tissues showed abnormal distribution of E-cadherin that could be rescued by overexpression of ELF but not Smad3 or Smad4. Our results identify a group of common lethal malignancies in which inactivation of TGF-b signaling, which is essential for tumor suppression, is disrupted by inactivation of the ELF adaptor protein.

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Section: Introductionmentioning

confidence: 99%

Critical interactions between TGF-β signaling/ELF, and E-cadherin/β-catenin mediated tumor suppression

Katuri

Tang

et al. 2006

Oncogene

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“…For example, ectopic p53 is rarely found in the cytoplasm unless PARC is also transfected into the cell [47]. Alternatively, microtubules play a role in tethering Smad proteins to the cytoplasm [48]. It is possible that there may exist such an analogous anchor(s) for EKLF in the erythroid cell.…”

Section: Discussionmentioning

confidence: 99%

Non-random subcellular distribution of variant EKLF in erythroid cells

Quadrini¹,

Gruzglin²,

Bieker³

2008

Experimental Cell Research

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EKLF protein plays a prominent role during erythroid development as a nuclear transcription factor. Not surprisingly, exogenous EKLF quickly localizes to the nucleus. However, using two different assays we have unexpectedly found that a substantial proportion of endogenous EKLF resides in the cytoplasm at steady state in all erythroid cells examined. While EKLF localization does not appear to change during either erythroid development or terminal differentiation, we find that the protein displays subtle yet distinct biochemical and functional differences depending on which subcellular compartment it is isolated from, with PEST sequences possibly playing a role in these differences. Localization is unaffected by inhibition of CRM1 activity and the two populations are not differentiated by stability. Heterokaryon assays demonstrate that EKLF is able to shuttle out of the nucleus although its nuclear re-entry is rapid. These studies suggest there is an unexplored role for EKLF in the cytoplasm that is separate from its well-characterized nuclear function.

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“…Thus, arginine 100 may play crucial roles in proper Smad4 folding or recognition by interacting proteins of the nuclear import or proteasome machineries, or both. Alternatively, the L43S and R100T mutants undergo selective cytoplasmic retention by anchoring proteins such as SARA or microtubule associating proteins (Dong et al, 2000;Tsukazaki et al, 1998). All such possibilities deserve further analysis.…”

Section: Missense Mutations In the Mh1 Domain Lead To Smad4 Instabilitymentioning

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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Microtubule Binding to Smads May Regulate TGFβ Activity

Cited by 258 publications

References 14 publications

Critical interactions between TGF-β signaling/ELF, and E-cadherin/β-catenin mediated tumor suppression

Critical interactions between TGF-β signaling/ELF, and E-cadherin/β-catenin mediated tumor suppression

Non-random subcellular distribution of variant EKLF in erythroid cells

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

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