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PMID: 22237159 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

BMP2 signals loss of epithelial character in epicardial cells but requires the Type III TGFβ receptor to promote invasion.

Cellular signalling ·Vol. 24 ·No. 5 ·2012-05-00 ·Pages 1012-22

Hill CR, Sanchez NS, Love JD, Arrieta JA, Hong CC, Brown CB, Austin AF, Barnett JV

Abstract

Coronary vessel development depends on a subpopulation of epicardial cells that undergo epithelial to mesenchymal transformation (EMT) and invade the subepicardial space and myocardium. These cells form the smooth muscle of the vessels and fibroblasts, but the mechanisms that regulate these processes are poorly understood. Mice lacking the Type III Transforming Growth Factor β Receptor (TGFβR3) die by E14.5 due to failed coronary vessel development accompanied by reduced epicardial cell invasion. BMP2 signals via TGFβR3 emphasizing the importance of determining the relative contributions of the canonical BMP signaling pathway and TGFβR3-dependent signaling to BMP2 responsiveness. Here we examined the role of TGFβR3 in BMP2 signaling in epicardial cells. Whereas TGFβ induced loss of epithelial character and smooth muscle differentiation, BMP2 induced an ALK3-dependent loss of epithelial character and modestly inhibited TGFβ-stimulated differentiation. Tgfbr3(-/-) cells respond to BMP2 indicating that TGFβR3 is not required. However, Tgfbr3(-/-) cells show decreased invasion in response to BMP2 and overexpression of TGFβR3 in Tgfbr3(-/-) cells rescued invasion. Invasion was dependent on ALK5, ALK2, ALK3, and Smad4. Expression of TGFβR3 lacking the 3 C-terminal amino acids required to interact with the scaffolding protein GIPC (GAIP-interacting protein, C terminus) did not rescue. Knockdown of GIPC in Tgfbr3(+/+) or Tgfbr3(-/-) cells rescued with TGFβR3 decreased BMP2-stimulated invasion confirming a requirement for TGFβR3/GIPC interaction. Our results reveal the relative roles of TGFβR3-dependent and TGFβR3-independent signaling in the actions of BMP2 on epicardial cell behavior and demonstrate the critical role of TGFβR3 in mediating BMP2-stimulated invasion.

MeSH Terms
Adaptor Proteins, Signal Transducing Animals Bone Morphogenetic Protein 2/physiology Carrier Proteins/metabolism Cell Differentiation Cell Movement Cells, Cultured Coronary Vessels/cytology,growth & development Epithelial Cells/metabolism,physiology Epithelial-Mesenchymal Transition Mice Mice, Knockout Myocytes, Smooth Muscle/metabolism,physiology Neuropeptides/metabolism Pericardium/cytology Proteoglycans/genetics,metabolism Receptors, Transforming Growth Factor beta/genetics,metabolism Smad Proteins/metabolism Transforming Growth Factors/physiology
Chemicals
Adaptor Proteins, Signal Transducing Bmp2 protein, mouse Bone Morphogenetic Protein 2 Carrier Proteins Gipc1 protein, mouse Neuropeptides Proteoglycans Receptors, Transforming Growth Factor beta Smad Proteins betaglycan Transforming Growth Factors
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Hill Cynthia R
Department of Pharmacology, Nashville, TN 37232, USA. cynthia.r.allison@vanderbilt.edu
Sanchez Nora S
Love Joseph D
Arrieta Julian A
Hong Charles C
Brown Christopher B
Austin Anita F
Barnett Joey V
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Article Info
Journal
Cellular signalling
Abbr.
Cell Signal
ISSN
1873-3913
DOI
10.1016/j.cellsig.2011.12.022
Email
cynthia.r.allison@vanderbilt.edu
Published
2012-05-00
Epub
2012-00-03
Pages
1012-22
Language
English
Region
England
NLM ID
8904683
PMCID
PMC3288519
Subset
IM
Grants
NHLBI NIH HHS · R01 HL085708-02S1 · United States
NHLBI NIH HHS · R01 HL104040 · United States
NHLBI NIH HHS · R01 HL085708-04 · United States
NHLBI NIH HHS · R25 HL96223 · United States
NHLBI NIH HHS · R25 HL096223-04 · United States
NHLBI NIH HHS · R25 HL096223 · United States
NHLBI NIH HHS · R01 HL085708 · United States
NHLBI NIH HHS · HL085708 · United States
NHLBI NIH HHS · R01 HL085708-03S1 · United States
External Links
PubMed source DOI: 10.1016/j.cellsig.2011.12.022 PMC Full Text View journal details
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