Degradation of Tiam1 by Casein Kinase 1 and the SCFβTrCPUbiquitin Ligase Controls the Duration of mTOR-S6K Signaling

Tiam1 (T-cell lymphoma invasion and metastasis 1) is a gua- nine 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 sys- tem 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 pro- teasomal 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.