PMID- 21212630
OWN - NLM
STAT- MEDLINE
DCOM- 20111021
LR  - 20211020
IS  - 1422-6421 (Electronic)
IS  - 1422-6405 (Print)
IS  - 1422-6405 (Linking)
VI  - 194
IP  - 1
DP  - 2011
TI  - BMP-2 and TGFbeta2 shared pathways regulate endocardial cell transformation.
PG  - 1-12
LID - 10.1159/000322035 [doi]
AB  - Valvular heart disease is a major cause of mortality and morbidity. Revealing the 
      cellular processes and molecules that regulate valve formation and remodeling is 
      required to develop effective therapies. A key step in valve formation during 
      heart development is the epithelial-mesenchymal transformation (EMT) of a 
      subpopulation of endocardial cells in the atrioventricular cushion (AVC). The 
      type III transforming growth factor-beta receptor (TGFbetaR3) regulates AVC endocardial 
      cell EMT in vitro and mesenchymal cell differentiation in vivo. Little is known 
      concerning the signaling mechanisms downstream of TGFbetaR3. Here we use endocardial 
      cell EMT in vitro to determine the role of 2 well-characterized downstream TGFbeta 
      signaling pathways in TGFbetaR3-dependent endocardial cell EMT. Targeting of Smad4, 
      the common mediator Smad, demonstrated that Smad signaling is required for EMT in 
      the AVC and TGFbetaR3-dependent EMT stimulated by TGFbeta2 or BMP-2. Although we show 
      that Smads 1, 2, 3, and 5 are required for AVC EMT, overexpression of Smad1 or 
      Smad3 is not sufficient to induce EMT. Consistent with the activation of the 
      Par6/Smurf1 pathway downstream of TGFbetaR3, targeting ALK5, Par6, or Smurf1 
      significantly inhibited EMT in response to either TGFbeta2 or BMP-2. The requirement 
      for ALK5 activity, Par6, and Smurf1 for TGFbetaR3-dependent endocardial cell EMT is 
      consistent with the documented role of this pathway in the dissolution of tight 
      junctions. Taken together, our data demonstrate that TGFbetaR3-dependent endocardial 
      cell EMT stimulated by either TGFbeta2 or BMP-2 requires Smad4 and the activation of 
      the Par6/Smurf1 pathway.
CI  - Copyright (c) 2011 S. Karger AG, Basel.
FAU - Townsend, Todd A
AU  - Townsend TA
AD  - Department of Pharmacology, Vanderbilt University Medical Center, Nashville, 
      Tenn., USA.
FAU - Robinson, Jamille Y
AU  - Robinson JY
FAU - Deig, Christopher R
AU  - Deig CR
FAU - Hill, Cynthia R
AU  - Hill CR
FAU - Misfeldt, Andrew
AU  - Misfeldt A
FAU - Blobe, Gerard C
AU  - Blobe GC
FAU - Barnett, Joey V
AU  - Barnett JV
LA  - eng
GR  - T32 GM007628/GM/NIGMS NIH HHS/United States
GR  - HL092551/HL/NHLBI NIH HHS/United States
GR  - GM062459/GM/NIGMS NIH HHS/United States
GR  - RL1 HL092551/HL/NHLBI NIH HHS/United States
GR  - GM007628/GM/NIGMS NIH HHS/United States
GR  - R25 GM062459/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110107
PL  - Switzerland
TA  - Cells Tissues Organs
JT  - Cells, tissues, organs
JID - 100883360
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Bone Morphogenetic Protein 2)
RN  - 0 (Smad4 Protein)
RN  - 0 (TGFB3 protein, human)
RN  - 0 (Transforming Growth Factor beta2)
RN  - 0 (Transforming Growth Factor beta3)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics/metabolism
MH  - Animals
MH  - Bone Morphogenetic Protein 2/*metabolism
MH  - Chick Embryo/metabolism
MH  - Endocardium/*cytology/metabolism
MH  - Humans
MH  - *Signal Transduction
MH  - Smad4 Protein/genetics/metabolism
MH  - Transfection
MH  - Transforming Growth Factor beta2/genetics/*metabolism
MH  - Transforming Growth Factor beta3/genetics/metabolism
PMC - PMC3128155
EDAT- 2011/01/08 06:00
MHDA- 2011/10/22 06:00
PMCR- 2012/06/01
CRDT- 2011/01/08 06:00
PHST- 2010/10/14 00:00 [accepted]
PHST- 2011/01/08 06:00 [entrez]
PHST- 2011/01/08 06:00 [pubmed]
PHST- 2011/10/22 06:00 [medline]
PHST- 2012/06/01 00:00 [pmc-release]
AID - 000322035 [pii]
AID - cto0194-0001 [pii]
AID - 10.1159/000322035 [doi]
PST - ppublish
SO  - Cells Tissues Organs. 2011;194(1):1-12. doi: 10.1159/000322035. Epub 2011 Jan 7.