PMID- 17671177
OWN - NLM
STAT- MEDLINE
DCOM- 20070911
LR  - 20220309
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 67
IP  - 15
DP  - 2007 Aug 1
TI  - Identification of S664 TSC2 phosphorylation as a marker for extracellular 
      signal-regulated kinase mediated mTOR activation in tuberous sclerosis and human 
      cancer.
PG  - 7106-12
AB  - Constitutive activation of extracellular signal-regulated kinases (Erk1/2) is 
      frequently implicated in human cancers. Recently, aberrantly activated Erk was 
      also found in brain lesions associated with tuberous sclerosis (TSC). We reported 
      previously that Erk might contribute to tumorigenesis by phosphorylating TSC2 at 
      specific residues, particularly S664. In our present study, 25 TSC-related 
      cortical tubers or subependymal giant cell astrocytomas, as well as tissue 
      microarrays of six types of human cancers, were analyzed for the expression of 
      phospho-Erk (pErk) 1/2, S664-phospho-TSC2 (pTSC2), and phospho-S6 (pS6) by 
      immunohistochemistry. We found that Erk-mediated TSC2 phosphorylation occurred at 
      a high incidence and positively correlated with mitogen-activated protein kinase 
      (MAPK) and mammalian target of rapamycin (mTOR) activation in TSC-associated 
      brain lesions as well as in various cancers. Interestingly, in certain types of 
      cancers (e.g., breast carcinoma and colon carcinoma), S664-pTSC2 seemed to be a 
      more sensitive marker than pErk. Furthermore, most of the pTSC2-positive samples 
      ( approximately 75%) were positive for pS6, but only 40% to 55% of the 
      pS6-positive tumors exhibited TSC2 phosphorylation. Our results show that S664 
      TSC2 phosphorylation is a marker for Erk-mediated (as opposed to Akt-mediated) 
      mTOR activation in TSC and human cancer. On the basis of these findings, TSC2 
      phosphorylation at S664 can be used to identify patients that may benefit from 
      antitumor therapy with MAPK and mTOR inhibitors. Importantly, our results 
      indicate that Erk-mediated phosphorylation and inactivation of TSC2 can be 
      critical in development of hamartomatous lesions in TSC and cancer pathogenesis.
FAU - Ma, Li
AU  - Ma L
AD  - Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial 
      Sloan-Kettering Cancer Center, New York, NY 10021, USA.
FAU - Teruya-Feldstein, Julie
AU  - Teruya-Feldstein J
FAU - Bonner, Pauline
AU  - Bonner P
FAU - Bernardi, Rosa
AU  - Bernardi R
FAU - Franz, David Neal
AU  - Franz DN
FAU - Witte, David
AU  - Witte D
FAU - Cordon-Cardo, Carlos
AU  - Cordon-Cardo C
FAU - Pandolfi, Pier Paolo
AU  - Pandolfi PP
LA  - eng
GR  - CA82328/CA/NCI NIH HHS/United States
GR  - CA84292/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (TSC2 protein, human)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Cells, Cultured
MH  - Extracellular Signal-Regulated MAP Kinases/*metabolism
MH  - Humans
MH  - Immunoblotting
MH  - Immunoprecipitation
MH  - Kidney/cytology
MH  - MAP Kinase Signaling System/*physiology
MH  - Neoplasms/etiology/*metabolism/pathology
MH  - Phosphorylation
MH  - Protein Kinases/*metabolism
MH  - Serine/metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Tissue Array Analysis
MH  - Transfection
MH  - Tuberous Sclerosis/etiology/*metabolism/pathology
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/*metabolism
EDAT- 2007/08/03 09:00
MHDA- 2007/09/12 09:00
CRDT- 2007/08/03 09:00
PHST- 2007/08/03 09:00 [pubmed]
PHST- 2007/09/12 09:00 [medline]
PHST- 2007/08/03 09:00 [entrez]
AID - 67/15/7106 [pii]
AID - 10.1158/0008-5472.CAN-06-4798 [doi]
PST - ppublish
SO  - Cancer Res. 2007 Aug 1;67(15):7106-12. doi: 10.1158/0008-5472.CAN-06-4798.