Degradation of Tiaml by casein kinase 1 and the SCFßTrCP ubiquitin ligase controls the duration of mTOR-S6K signaling

Abstract

Tiaml (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, Tiaml is degraded by the ubiquitin-proteasome system via the SCFßTrCP ubiquitin ligase. Mitogenic stimulation triggers the binding of Tiaml to the F-box protein ßTrCP via its degron sequence and subsequent Tiaml ubiquitylation and proteasomal degradation. The proteolysis of Tiaml is prevented by ßTrCP silencing, inhibition of CK1 and MEK, or mutation of the Tiaml degron site. Expression of a stable Tiaml mutant that is unable to interact with ßTrCP results in sustained activation of the mTOR/S6K signaling and increased apoptotic cell death. We propose that the SCFßTrCP-mediated degradation of Tiaml controls the duration of the mTOR-S6K signaling pathway in response to mitogenic stimuli.