PMID- 22356909
OWN - NLM
STAT- MEDLINE
DCOM- 20120606
LR  - 20221123
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 287
IP  - 15
DP  - 2012 Apr 6
TI  - Intestinal cell kinase (ICK) promotes activation of mTOR complex 1 (mTORC1) 
      through phosphorylation of Raptor Thr-908.
PG  - 12510-9
LID - 10.1074/jbc.M111.302117 [doi]
AB  - Intestinal cell kinase (ICK), named after its cloning origin, the intestine, is 
      actually a ubiquitously expressed and highly conserved serine/threonine protein 
      kinase. Recently we reported that ICK supports cell proliferation and G(1) cell 
      cycle progression. ICK deficiency significantly disrupted the mammalian target of 
      rapamycin (mTOR) complex 1 (mTORC1) signaling events. However, the biological 
      substrates that mediate the downstream signaling effects of ICK in proliferation 
      and the molecular mechanisms by which ICK interacts with mTORC1 are not well 
      defined. Our prior studies also provided biochemical evidence that ICK interacts 
      with the mTOR/Raptor complex in cells and phosphorylates Raptor in vitro. In this 
      report, we investigated whether and how ICK targets Raptor to regulate the 
      activity of mTORC1. Using the ICK substrate consensus sequence 
      [R-P-X-S/T-P/A/T/S], we identified a putative phosphorylation site, RPGT908T, for 
      ICK in human Raptor. By mass spectrometry and a phospho-specific antibody, we 
      showed that Raptor Thr-908 is a novel in vivo phosphorylation site. ICK is able 
      to phosphorylate Raptor Thr-908 both in vitro and in vivo and when Raptor exists 
      in protein complexes with or without mTOR. Although expression of the Raptor 
      T908A mutant did not affect the mTORC1 integrity, it markedly impaired the mTORC1 
      activation by insulin or by overexpression of the small GTP-binding protein RheB 
      under nutrient starvation. Our findings demonstrate an important role for ICK in 
      modulating the activity of mTORC1 through phosphorylation of Raptor Thr-908 and 
      thus implicate a potential signaling mechanism by which ICK regulates cell 
      proliferation and division.
FAU - Wu, Di
AU  - Wu D
AD  - Department of Medicine, University of Virginia, Charlottesville, Virginia 22908, 
      USA.
FAU - Chapman, Jessica R
AU  - Chapman JR
FAU - Wang, Lifu
AU  - Wang L
FAU - Harris, Thurl E
AU  - Harris TE
FAU - Shabanowitz, Jeffrey
AU  - Shabanowitz J
FAU - Hunt, Donald F
AU  - Hunt DF
FAU - Fu, Zheng
AU  - Fu Z
LA  - eng
GR  - K01 DK082614/DK/NIDDK NIH HHS/United States
GR  - GM37537/GM/NIGMS NIH HHS/United States
GR  - R01 GM037537/GM/NIGMS NIH HHS/United States
GR  - P30 CA044579/CA/NCI NIH HHS/United States
GR  - DK082614/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20120222
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Neuropeptides)
RN  - 0 (Oligopeptides)
RN  - 0 (Peptide Fragments)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proteins)
RN  - 0 (RHEB protein, human)
RN  - 0 (RPTOR protein, human)
RN  - 0 (Ras Homolog Enriched in Brain Protein)
RN  - 0 (Regulatory-Associated Protein of mTOR)
RN  - 1114-81-4 (Phosphothreonine)
RN  - EC 2.7.1.- (CILK1 protein, human)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 1)
RN  - EC 3.6.5.2 (Monomeric GTP-Binding Proteins)
SB  - IM
MH  - 3T3-L1 Cells
MH  - Adaptor Proteins, Signal Transducing/chemistry/genetics/*metabolism
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Animals
MH  - Cell Cycle Proteins
MH  - Cell Proliferation
MH  - Consensus Sequence
MH  - G1 Phase
MH  - HEK293 Cells
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Molecular Sequence Data
MH  - Monomeric GTP-Binding Proteins/metabolism
MH  - Multiprotein Complexes
MH  - Mutagenesis, Site-Directed
MH  - Neuropeptides/metabolism
MH  - Oligopeptides/chemistry
MH  - Peptide Fragments/chemistry
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Phosphothreonine/metabolism
MH  - Protein Binding
MH  - Protein Serine-Threonine Kinases/chemistry/metabolism/*physiology
MH  - Proteins/*metabolism
MH  - Ras Homolog Enriched in Brain Protein
MH  - Regulatory-Associated Protein of mTOR
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - TOR Serine-Threonine Kinases
PMC - PMC3321000
EDAT- 2012/02/24 06:00
MHDA- 2012/06/07 06:00
PMCR- 2013/04/06
CRDT- 2012/02/24 06:00
PHST- 2012/02/24 06:00 [entrez]
PHST- 2012/02/24 06:00 [pubmed]
PHST- 2012/06/07 06:00 [medline]
PHST- 2013/04/06 00:00 [pmc-release]
AID - S0021-9258(20)53178-5 [pii]
AID - M111.302117 [pii]
AID - 10.1074/jbc.M111.302117 [doi]
PST - ppublish
SO  - J Biol Chem. 2012 Apr 6;287(15):12510-9. doi: 10.1074/jbc.M111.302117. Epub 2012 
      Feb 22.