PMID- 23359693
OWN - NLM
STAT- MEDLINE
DCOM- 20130408
LR  - 20211203
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 110
IP  - 7
DP  - 2013 Feb 12
TI  - Regulation of Hippo pathway by mitogenic growth factors via phosphoinositide 
      3-kinase and phosphoinositide-dependent kinase-1.
PG  - 2569-74
LID - 10.1073/pnas.1216462110 [doi]
AB  - The Hippo signaling pathway inhibits cell growth and regulates organ size through 
      a kinase cascade that leads to the phosphorylation and nuclear exclusion of the 
      growth-promoting transcriptional coactivator Yes-associated protein (YAP)/Yorkie. 
      It mediates contact inhibition of cell growth downstream of cadherin adhesion 
      molecules and other cell surface proteins. Contact inhibition is often 
      antagonized by mitogenic growth factor signaling. We report an important 
      mechanism for this antagonism, inhibition of Hippo pathway signaling by mitogenic 
      growth factors. EGF treatment of immortalized mammary cells triggers the rapid 
      translocation of YAP into the nucleus along with YAP dephosphorylation, both of 
      which depend on Lats, the terminal kinase in the Hippo pathway. A small-molecule 
      inhibitor screen of downstream effector pathways shows that EGF receptor inhibits 
      the Hippo pathway through activation of PI3-kinase (PI3K) and 
      phosphoinositide-dependent kinase (PDK1), but independent of AKT activity. The 
      PI3K-PDK1 pathway also mediates YAP nuclear translocation downstream of 
      lysophosphatidic acid and serum as a result of constitutive oncogenic activation 
      of PI3K. PDK1 associates with the core Hippo pathway-kinase complex through the 
      scaffold protein Salvador. The entire Hippo core complex dissociates in response 
      to EGF signaling in a PI3K-PDK1-dependent manner, leading to inactivation of 
      Lats, dephosphorylation of YAP, and YAP nuclear accumulation and transcriptional 
      activation of its target gene, CTGF. These findings show that an important 
      activity of mitogenic signaling pathways is to inactivate the growth-inhibitory 
      Hippo pathway and provide a mechanism for antagonism between contact inhibition 
      and growth factor action.
FAU - Fan, Run
AU  - Fan R
AD  - University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
FAU - Kim, Nam-Gyun
AU  - Kim NG
FAU - Gumbiner, Barry M
AU  - Gumbiner BM
LA  - eng
GR  - P30 CA044579/CA/NCI NIH HHS/United States
GR  - R01 GM098615/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130128
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Androstadienes)
RN  - 0 (Cadherins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Phosphoproteins)
RN  - 0 (SAV1 protein, human)
RN  - 0 (Transcription Factors)
RN  - 0 (YAP-Signaling Proteins)
RN  - 0 (YAP1 protein, human)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 2.7.1.- (LATS1 protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.1 (3-Phosphoinositide-Dependent Protein Kinases)
RN  - EC 2.7.11.1 (PDPK1 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
RN  - EC 2.7.11.25 (MAP3K10 protein, human)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - 3-Phosphoinositide-Dependent Protein Kinases
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - Androstadienes
MH  - Blotting, Western
MH  - Cadherins/metabolism
MH  - Cell Cycle Proteins/metabolism
MH  - Cell Line
MH  - Chromatin Immunoprecipitation
MH  - Contact Inhibition/genetics/*physiology
MH  - Epidermal Growth Factor/*metabolism
MH  - ErbB Receptors/metabolism
MH  - Humans
MH  - Immunoprecipitation
MH  - MAP Kinase Kinase Kinases/*metabolism
MH  - Microscopy, Fluorescence
MH  - Multiprotein Complexes/*metabolism
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Polymerase Chain Reaction
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Signal Transduction/*physiology
MH  - Transcription Factors
MH  - Wortmannin
MH  - YAP-Signaling Proteins
PMC - PMC3574943
COIS- The authors declare no conflict of interest.
EDAT- 2013/01/30 06:00
MHDA- 2013/04/09 06:00
PMCR- 2013/08/12
CRDT- 2013/01/30 06:00
PHST- 2013/01/30 06:00 [entrez]
PHST- 2013/01/30 06:00 [pubmed]
PHST- 2013/04/09 06:00 [medline]
PHST- 2013/08/12 00:00 [pmc-release]
AID - 1216462110 [pii]
AID - 201216462 [pii]
AID - 10.1073/pnas.1216462110 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2013 Feb 12;110(7):2569-74. doi: 
      10.1073/pnas.1216462110. Epub 2013 Jan 28.