Hgs (Hrs), a FYVE Domain Protein, Is Involved in Smad Signaling through Cooperation with SARA

Miura, Shigeto; Takeshita, Toru; Asao, Hironobu; Kimura, Yutaka; Murata, Kazuko; Sasaki, Yoshiyuki; Hanai, Jun‐ichi; Beppu, Hideyuki; Tsukazaki, Tomoo; Wrana, Jeffrey L.; Miyazono, Kohei; Sugamura, Kazuo

doi:10.1128/mcb.20.24.9346-9355.2000

Cited by 165 publications

(140 citation statements)

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“…Notably, SARA mutants that mislocalize Smad2 result in inhibition of TGF-␤ signaling, suggesting that this recruitment is important to signaling. Localization of Smad2 to endosomes may be facilitated by Hrs which, like SARA, contains an FYVE domain and can bind Smad2 (Miura et al 2000). Recruitment of Smad2 to the internalized receptor complex is significantly increased in cells cotransfected with hrs and SARA compared to either gene alone, suggesting that Hrs and SARA cooperate to promote Smad2 activation at the endosome, thereby facilitating TGF-␤ signaling.…”

Section: Regulation Of Smad Proteinsmentioning

confidence: 97%

When cell biology meets development: endocytic regulation of signaling pathways

2002

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Section: Regulation Of Smad Proteinsmentioning

confidence: 97%

When cell biology meets development: endocytic regulation of signaling pathways

2002

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“…1); the binding of SARA and Smad4 with activated R-Smad are mutually exclusive. Hrs/ Hgs, another FYVE domain containing protein, was also shown to participate in Smad presentation to receptor and to synergize with SARA in stimulating TGF-b/Smad signaling (Miura et al, 2000). Hrs/Hgs binds phosphatidylinositol 3-phosphate (PtdIns(3)P) and is localized on early endosomes (Burd and Emr, 1998;Gaullier et al, 1998;Patki et al, 1998).…”

Section: Regulation Of Smad Activation Tgf-b Receptor-induced Smad Acmentioning

confidence: 99%

Regulation of cell proliferation by Smad proteins

Dijke

Goumans

Itoh

2002

Journal Cellular Physiology

399

278

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Transforming growth factor-b (TGF-b) family members which include TGF-bs, activins, and bone morphogenetic proteins (BMPs) regulate a broad spectrum of biological responses on a large variety of cell types. TGF-b family members initiate their cellular responses by binding to distinct receptors with intrinsic serine/ threonine kinase activity and activation of speci®c downstream intracellular effectors termed Smad proteins. Smads relay the signal from the cell membrane to the nucleus, where they affect the transcription of target genes. Smad activation, subcellular distribution, and stability have been found to be intricately regulated and a broad array of transcription factors have been identi®ed as Smad partners. Important activities of TGF-b are its potent anti-mitogenic and pro-apoptotic effects that, at least in part, are mediated via Smad proteins. Escape from TGF-b/ Smad-induced growth inhibition and apoptosis is frequently observed in tumors. Certain Smads have been found to be mutated in speci®c types of cancer and gene ablation of particular Smads in mice has revealed increased rate of tumorigenesis. In late stage tumors, TGF-b has been shown to function as a tumor promoter. TGFb can stimulate the de-differentiation of epithelial cells to malignant invasive and metastatic ®broblastic cells. Interestingly, TGF-b may mediate these effects directly on tumor cells via subverted Smad-dependent and/or Smad-independent pathways.

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“…It was shown that SARA functions as a scaffold protein by specifically interacting with Smad2/3 and TGF-b receptors to facilitate Smad2/3 phosphorylation by the TGF-b receptor [71]. Similarly, Hrs can interact with Smad2 and cooperate with SARA to promote activin-mediated activation of Smad2 [72]. Endofin can also facilitate TGF-b signaling.…”

Section: Tgf-β Signaling In Endosomesmentioning

confidence: 99%

“…Several positive regulators of TGF-b signaling are localized in endosomes. For instance, three FYVE (Fab1, YOTB/ZK632.12, Vac1, and EEA1) domain-containing proteins, SARA, endofin and Hrs/ Hgs ((hepatocyte growth factor-regulated tyrosine kinase substrate), have been suggested to promote TGF-b, activin and decapentaplegic (Dpp) signaling [71][72][73][74][75]. The FYVE domain is a zinc-binding motif known to bind phosphatidylinositol 3-phosphate, a lipid enriched in early endosomes, and can specifically recruit the FYVEdomain-containing proteins to early endosomes [76].…”

Section: Tgf-β Signaling In Endosomesmentioning

confidence: 99%