期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 40, 页码 27400-27409出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.575571
关键词
E3 Ubiquitin Ligase; Proteasome; Proteolysis; Signal Transduction; Ubiquitin; Tiam1; betaTrCP; mTOR-S6K Signaling
资金
- Royal Dutch Academy of Arts and Sciences (KNAW)
- Dutch Cancer Society (KWF)
- Cancer Genomics Centre
- European Union under Marie Curie Actions
- Netherlands Proteomics Center
Background: The guanine nucleotide exchange factor Tiam1 regulates the activity of the small GTPase Rac1, a crucial regulator of cell adhesion, proliferation, and survival. Results: The SCFTrCP ubiquitin ligase in cooperation with CK1 targets Tiam1 for proteasome-dependent degradation. Conclusion: Tiam1 degradation is required to terminate the mTOR-S6K signaling pathway. Significance: Tiam1 degradation controls the duration of mTOR-S6K signaling in response to mitogens. Tiam1 (T-cell lymphoma invasion and metastasis 1) is a guanine nucleotide exchange factor that specifically controls the activity of the small GTPase Rac, a key regulator of cell adhesion, proliferation, and survival. Here, we report that in response to mitogens, Tiam1 is degraded by the ubiquitin-proteasome system via the SCFTrCP ubiquitin ligase. Mitogenic stimulation triggers the binding of Tiam1 to the F-box protein TrCP via its degron sequence and subsequent Tiam1 ubiquitylation and proteasomal degradation. The proteolysis of Tiam1 is prevented by TrCP silencing, inhibition of CK1 and MEK, or mutation of the Tiam1 degron site. Expression of a stable Tiam1 mutant that is unable to interact with TrCP results in sustained activation of the mTOR/S6K signaling and increased apoptotic cell death. We propose that the SCFTrCP-mediated degradation of Tiam1 controls the duration of the mTOR-S6K signaling pathway in response to mitogenic stimuli.
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