PMID- 20974850
OWN - NLM
STAT- MEDLINE
DCOM- 20110131
LR  - 20211203
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 286
IP  - 1
DP  - 2011 Jan 7
TI  - Negative regulation of TGFbeta signaling by the kinase LKB1 and the scaffolding 
      protein LIP1.
PG  - 341-53
LID - 10.1074/jbc.M110.190660 [doi]
AB  - Signal transduction by the Smad pathway elicits critical biological responses to 
      many extracellular polypeptide factors, including TGFbeta and bone morphogenetic 
      protein. Regulation of Smad signaling imparts several cytoplasmic and nuclear 
      mechanisms, some of which entail protein phosphorylation. Previous work 
      established a protein complex between Smad4 and the scaffolding protein 
      LKB1-interacting protein 1 (LIP1). LKB1 is a well studied tumor suppressor kinase 
      that regulates cell growth and polarity. Here, we analyzed the LKB1-LIP1 and the 
      Smad4-LIP1 protein complexes and found that LIP1 can self-oligomerize. We further 
      demonstrate that LKB1 is capable of phosphorylating Smad4 on Thr(77) of its 
      DNA-binding domain. LKB1 inhibits Smad4 from binding to either TGFbeta- or bone 
      morphogenetic protein-specific promoter sequences, which correlates with the 
      negative regulatory effect LKB1 exerts on Smad4-dependent transcription. 
      Accordingly, LKB1 negatively regulates TGFbeta gene responses and 
      epithelial-mesenchymal transition. Thus, LKB1 and LIP1 provide negative control 
      of TGFbeta signaling.
FAU - Moren, Anita
AU  - Moren A
AD  - Ludwig Institute for Cancer Research, Uppsala University, Box 595, Biomedical 
      Center, Uppsala University, SE-751 24 Uppsala, Sweden.
FAU - Raja, Erna
AU  - Raja E
FAU - Heldin, Carl-Henrik
AU  - Heldin CH
FAU - Moustakas, Aristidis
AU  - Moustakas A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101025
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (STK11IP protein, human)
RN  - 0 (Smad4 Protein)
RN  - 0 (Transforming Growth Factor beta)
RN  - 2ZD004190S (Threonine)
RN  - 9007-49-2 (DNA)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (STK11 protein, human)
RN  - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinase Kinases
MH  - Adaptor Proteins, Signal Transducing/chemistry/*metabolism
MH  - Amino Acid Sequence
MH  - Animals
MH  - Cell Line, Tumor
MH  - DNA/metabolism
MH  - Epithelial-Mesenchymal Transition/drug effects
MH  - Humans
MH  - Mice
MH  - Molecular Sequence Data
MH  - Phosphorylation
MH  - Protein Multimerization
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Protein Structure, Quaternary
MH  - *Signal Transduction
MH  - Smad4 Protein/chemistry/metabolism
MH  - Threonine/metabolism
MH  - Transcription, Genetic
MH  - Transforming Growth Factor beta/*antagonists & 
      inhibitors/*metabolism/pharmacology
PMC - PMC3012991
EDAT- 2010/10/27 06:00
MHDA- 2011/02/01 06:00
PMCR- 2010/10/25
CRDT- 2010/10/27 06:00
PHST- 2010/10/27 06:00 [entrez]
PHST- 2010/10/27 06:00 [pubmed]
PHST- 2011/02/01 06:00 [medline]
PHST- 2010/10/25 00:00 [pmc-release]
AID - S0021-9258(20)54226-9 [pii]
AID - M110.190660 [pii]
AID - 10.1074/jbc.M110.190660 [doi]
PST - ppublish
SO  - J Biol Chem. 2011 Jan 7;286(1):341-53. doi: 10.1074/jbc.M110.190660. Epub 2010 
      Oct 25.