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

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

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)27400-27409
Number of pages10
JournalJournal of Biological Chemistry
Volume289
Issue number40
DOIs
Publication statusPublished - 3 Oct 2014
Externally publishedYes

Fingerprint

Casein Kinase I
Ligases
Ubiquitin
F-Box Proteins
Proteolysis
Guanine Nucleotide Exchange Factors
Degradation
Monomeric GTP-Binding Proteins
T-cells
T-Cell Lymphoma
Ubiquitination
Cell adhesion
Mitogen-Activated Protein Kinase Kinases
Cell death
Proteasome Endopeptidase Complex
Mitogens
Cell Adhesion
Cell Survival
Cell Death
Chemical activation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Degradation of Tiaml by casein kinase 1 and the SCFßTrCP ubiquitin ligase controls the duration of mTOR-S6K signaling. / Magliozzi, Roberto; Kim, Jihoon; Teck Yew, Low; Heck, Albert J R; Guardavaccaro, Daniele.

In: Journal of Biological Chemistry, Vol. 289, No. 40, 03.10.2014, p. 27400-27409.

Research output: Contribution to journalArticle

Magliozzi, Roberto ; Kim, Jihoon ; Teck Yew, Low ; Heck, Albert J R ; Guardavaccaro, Daniele. / Degradation of Tiaml by casein kinase 1 and the SCFßTrCP ubiquitin ligase controls the duration of mTOR-S6K signaling. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 40. pp. 27400-27409.
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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 SCF{\ss}TrCP ubiquitin ligase. Mitogenic stimulation triggers the binding of Tiaml to the F-box protein {\ss}TrCP via its degron sequence and subsequent Tiaml ubiquitylation and proteasomal degradation. The proteolysis of Tiaml is prevented by {\ss}TrCP 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 {\ss}TrCP results in sustained activation of the mTOR/S6K signaling and increased apoptotic cell death. We propose that the SCF{\ss}TrCP-mediated degradation of Tiaml controls the duration of the mTOR-S6K signaling pathway in response to mitogenic stimuli.",
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