Degradation of Tiam1 by casein kinase 1 and the SCFβTrCP ubiquitin ligase controls the duration of mTOR-S6K signaling

Roberto Magliozzi, Jihoon Kim, Teck Yew Low, Albert J R Heck, Daniele Guardavaccaro

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

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 SCF(βTrCP) ubiquitin ligase. Mitogenic stimulation triggers the binding of Tiam1 to the F-box protein βTrCP via its degron sequence and subsequent Tiam1 ubiquitylation and proteasomal degradation. The proteolysis of Tiam1 is prevented by βTrCP 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 βTrCP results in sustained activation of the mTOR/S6K signaling and increased apoptotic cell death. We propose that the SCF(βTrCP)-mediated degradation of Tiam1 controls the duration of the mTOR-S6K signaling pathway in response to mitogenic stimuli.

Original languageEnglish
Pages (from-to)27400-9
Number of pages10
JournalThe Journal of biological chemistry
Volume289
Issue number40
DOIs
Publication statusPublished - 03 Oct 2014

Keywords

  • Casein Kinase I
  • Guanine Nucleotide Exchange Factors
  • Humans
  • Phosphorylation
  • Protein Binding
  • Proteolysis
  • Ribosomal Protein S6 Kinases, 70-kDa
  • SKP Cullin F-Box Protein Ligases
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • beta-Transducin Repeat-Containing Proteins

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