PMID- 16244323
OWN - NLM
STAT- MEDLINE
DCOM- 20060523
LR  - 20231120
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 14 Spec No. 2
DP  - 2005 Oct 15
TI  - Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways.
PG  - R251-8
AB  - Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that is 
      characterized by benign tumors (hamartomas and hamartias) involving multiple 
      organ systems, due to inactivating mutations in TSC1 or TSC2. Here, we review 
      recent advances in our understanding of the growth and signaling functions of the 
      TSC1 and TSC2 proteins. Led by seminal studies in Drosophila, the TSC1/TSC2 
      complex has been positioned in an ancestrally conserved signaling pathway that 
      regulates cell growth. TSC1/TSC2 receives inputs from at least three major 
      signaling pathways in the form of kinase-mediated phosphorylation events that 
      regulate its function as a GTPase activating protein (GAP): the PI3K-Akt pathway, 
      the ERK1/2-RSK1 pathway and the LKB1-AMPK pathway. TSC1/TSC2 functions as a GAP 
      towards Rheb, which is a major regulator of the mammalian target of rapamycin 
      (mTOR). In the absence of either TSC1 or TSC2, high levels of Rheb-GTP lead to 
      constitutive activation of mTOR-raptor signaling, thereby leading to enhanced and 
      deregulated protein synthesis and cell growth. As a specific inhibitor of mTOR, 
      rapamycin has therapeutic potential for the treatment of TSC hamartomas.
FAU - Kwiatkowski, David J
AU  - Kwiatkowski DJ
AD  - Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, One 
      Blackfan Circle, 6th Floor, Room 216, Boston, MA 02115, USA. 
      dk@rics.bwh.harvard.edu
FAU - Manning, Brendan D
AU  - Manning BD
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PT  - Review
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (GTPase-Activating Proteins)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Cell Proliferation
MH  - Cell Size
MH  - GTPase-Activating Proteins/*metabolism
MH  - Hamartoma/etiology
MH  - Magnetic Resonance Imaging
MH  - Models, Biological
MH  - Protein Kinases/metabolism
MH  - Signal Transduction/*genetics
MH  - TOR Serine-Threonine Kinases
MH  - Tuberous Sclerosis/*metabolism
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/metabolism/physiology
RF  - 97
EDAT- 2005/10/26 09:00
MHDA- 2006/05/24 09:00
CRDT- 2005/10/26 09:00
PHST- 2005/10/26 09:00 [pubmed]
PHST- 2006/05/24 09:00 [medline]
PHST- 2005/10/26 09:00 [entrez]
AID - 14/suppl_2/R251 [pii]
AID - 10.1093/hmg/ddi260 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:R251-8. doi: 10.1093/hmg/ddi260.