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

TY - JOUR

T1 - Degradation of Tiam1 by casein kinase 1 and the SCFβTrCP ubiquitin ligase controls the duration of mTOR-S6K signaling

AU - Magliozzi, Roberto

AU - Kim, Jihoon

AU - Low, Teck Yew

AU - Heck, Albert J R

AU - Guardavaccaro, Daniele

N1 - © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

PY - 2014/10/3

Y1 - 2014/10/3

N2 - 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.

AB - 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.

KW - Casein Kinase I

KW - Guanine Nucleotide Exchange Factors

KW - Humans

KW - Phosphorylation

KW - Protein Binding

KW - Proteolysis

KW - Ribosomal Protein S6 Kinases, 70-kDa

KW - SKP Cullin F-Box Protein Ligases

KW - Signal Transduction

KW - TOR Serine-Threonine Kinases

KW - beta-Transducin Repeat-Containing Proteins

U2 - 10.1074/jbc.M114.575571

DO - 10.1074/jbc.M114.575571

M3 - Article

C2 - 25124033

SN - 0021-9258

VL - 289

SP - 27400

EP - 27409

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 40

ER -