Degradation of Tiam1 by Casein Kinase 1 and the SCFβTrCP Ubiquitin Ligase Controls the Duration of mTOR-S6K signaling.

T-cell lymphoma invasion and metastasis 1 (Tiam1) 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 SCFbetaTrCP ...
ubiquitin ligase. Mitogenic stimulation triggers the binding of Tiam1 to the F-box protein betaTrCP via its degron sequence and subsequent Tiam1 ubiquitylation and proteasomal degradation. The proteolysis of Tiam1 is prevented by betaTrCP 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 betaTrCP results in sustained activation of the mTOR/S6K signaling and increased apoptotic cell death. We propose that the SCFbetaTrCP-mediated degradation of Tiam1 controls the duration of the mTOR-S6K signaling pathway in response to mitogenic stimuli.
J. Biol. Chem.
Date: Aug. 14, 2014
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