The cysteine-rich domain protein KCP is a suppressor of transforming growth factor β/activin signaling in renal epithelia

Jingmei Lin, Sanjeevkumar R. Patel, Min Wang, Gregory R. Dressler

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

The transforming growth factor β (TGF-β) superfamily, including the bone morphogenetic protein (BMP) and TGF-β/activin A subfamilies, is regulated by secreted proteins able to sequester or present ligands to receptors. KCP is a secreted, cysteine-rich (CR) protein with similarity to mouse Chordin and Xenopus laevis Kielin. KCP is an enhancer of BMP signaling in vertebrates and interacts with BMPs and the BMP type I receptor to promote receptor-ligand interactions. Mice homozygous for a KCP null allele are hypersensitive to developing renal interstitial fibrosis, a disease stimulated by TGF-β but inhibited by BMP7. In this report, the elects of KCP on TGF-β/activin A signaling are examined. In contrast to the enhancing effect on BMPs, KCP inhibits both activin A- and TGF-β1-mediated signaling through the Smad2/3 pathway. These inhibitory effects of KCP are mediated in a paracrine manner, suggesting that direct binding of KCP to TGF-β1 or activin A can block the interactions with prospective receptors. Consistent with this inhibitory effect, primary renal epithelial cells from KCP mutant cells are hypersensitive to TGF-β and exhibit increased apoptosis, dissociation of cadherin-based cell junctions, and expression of smooth muscle actin. Furthermore, KCP null animals show elevated levels of phosphorylated Smad2 after renal injury. The ability to enhance BMP signaling while suppressing TGF-β activation indicates a critical role for KCP in modulating the responses between these anti- and profibrotic cytokines in the initiation and progression of renal interstitial fibrosis.

Original languageEnglish (US)
Pages (from-to)4577-4585
Number of pages9
JournalMolecular and Cellular Biology
Volume26
Issue number12
DOIs
StatePublished - Jun 2006
Externally publishedYes

Fingerprint

Activins
Transforming Growth Factors
Cysteine
Epithelium
Kidney
Bone Morphogenetic Proteins
Fibrosis
Type I Bone Morphogenetic Protein Receptors
Ligands
Intercellular Junctions
Protein Domains
Xenopus laevis
Cadherins
Smooth Muscle
Vertebrates
Actins
Proteins
Epithelial Cells
Alleles
Apoptosis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

The cysteine-rich domain protein KCP is a suppressor of transforming growth factor β/activin signaling in renal epithelia. / Lin, Jingmei; Patel, Sanjeevkumar R.; Wang, Min; Dressler, Gregory R.

In: Molecular and Cellular Biology, Vol. 26, No. 12, 06.2006, p. 4577-4585.

Research output: Contribution to journalArticle

@article{404139bd51624d4da95a5d33511fd9e4,
title = "The cysteine-rich domain protein KCP is a suppressor of transforming growth factor β/activin signaling in renal epithelia",
abstract = "The transforming growth factor β (TGF-β) superfamily, including the bone morphogenetic protein (BMP) and TGF-β/activin A subfamilies, is regulated by secreted proteins able to sequester or present ligands to receptors. KCP is a secreted, cysteine-rich (CR) protein with similarity to mouse Chordin and Xenopus laevis Kielin. KCP is an enhancer of BMP signaling in vertebrates and interacts with BMPs and the BMP type I receptor to promote receptor-ligand interactions. Mice homozygous for a KCP null allele are hypersensitive to developing renal interstitial fibrosis, a disease stimulated by TGF-β but inhibited by BMP7. In this report, the elects of KCP on TGF-β/activin A signaling are examined. In contrast to the enhancing effect on BMPs, KCP inhibits both activin A- and TGF-β1-mediated signaling through the Smad2/3 pathway. These inhibitory effects of KCP are mediated in a paracrine manner, suggesting that direct binding of KCP to TGF-β1 or activin A can block the interactions with prospective receptors. Consistent with this inhibitory effect, primary renal epithelial cells from KCP mutant cells are hypersensitive to TGF-β and exhibit increased apoptosis, dissociation of cadherin-based cell junctions, and expression of smooth muscle actin. Furthermore, KCP null animals show elevated levels of phosphorylated Smad2 after renal injury. The ability to enhance BMP signaling while suppressing TGF-β activation indicates a critical role for KCP in modulating the responses between these anti- and profibrotic cytokines in the initiation and progression of renal interstitial fibrosis.",
author = "Jingmei Lin and Patel, {Sanjeevkumar R.} and Min Wang and Dressler, {Gregory R.}",
year = "2006",
month = "6",
doi = "10.1128/MCB.02127-05",
language = "English (US)",
volume = "26",
pages = "4577--4585",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "12",

}

TY - JOUR

T1 - The cysteine-rich domain protein KCP is a suppressor of transforming growth factor β/activin signaling in renal epithelia

AU - Lin, Jingmei

AU - Patel, Sanjeevkumar R.

AU - Wang, Min

AU - Dressler, Gregory R.

PY - 2006/6

Y1 - 2006/6

N2 - The transforming growth factor β (TGF-β) superfamily, including the bone morphogenetic protein (BMP) and TGF-β/activin A subfamilies, is regulated by secreted proteins able to sequester or present ligands to receptors. KCP is a secreted, cysteine-rich (CR) protein with similarity to mouse Chordin and Xenopus laevis Kielin. KCP is an enhancer of BMP signaling in vertebrates and interacts with BMPs and the BMP type I receptor to promote receptor-ligand interactions. Mice homozygous for a KCP null allele are hypersensitive to developing renal interstitial fibrosis, a disease stimulated by TGF-β but inhibited by BMP7. In this report, the elects of KCP on TGF-β/activin A signaling are examined. In contrast to the enhancing effect on BMPs, KCP inhibits both activin A- and TGF-β1-mediated signaling through the Smad2/3 pathway. These inhibitory effects of KCP are mediated in a paracrine manner, suggesting that direct binding of KCP to TGF-β1 or activin A can block the interactions with prospective receptors. Consistent with this inhibitory effect, primary renal epithelial cells from KCP mutant cells are hypersensitive to TGF-β and exhibit increased apoptosis, dissociation of cadherin-based cell junctions, and expression of smooth muscle actin. Furthermore, KCP null animals show elevated levels of phosphorylated Smad2 after renal injury. The ability to enhance BMP signaling while suppressing TGF-β activation indicates a critical role for KCP in modulating the responses between these anti- and profibrotic cytokines in the initiation and progression of renal interstitial fibrosis.

AB - The transforming growth factor β (TGF-β) superfamily, including the bone morphogenetic protein (BMP) and TGF-β/activin A subfamilies, is regulated by secreted proteins able to sequester or present ligands to receptors. KCP is a secreted, cysteine-rich (CR) protein with similarity to mouse Chordin and Xenopus laevis Kielin. KCP is an enhancer of BMP signaling in vertebrates and interacts with BMPs and the BMP type I receptor to promote receptor-ligand interactions. Mice homozygous for a KCP null allele are hypersensitive to developing renal interstitial fibrosis, a disease stimulated by TGF-β but inhibited by BMP7. In this report, the elects of KCP on TGF-β/activin A signaling are examined. In contrast to the enhancing effect on BMPs, KCP inhibits both activin A- and TGF-β1-mediated signaling through the Smad2/3 pathway. These inhibitory effects of KCP are mediated in a paracrine manner, suggesting that direct binding of KCP to TGF-β1 or activin A can block the interactions with prospective receptors. Consistent with this inhibitory effect, primary renal epithelial cells from KCP mutant cells are hypersensitive to TGF-β and exhibit increased apoptosis, dissociation of cadherin-based cell junctions, and expression of smooth muscle actin. Furthermore, KCP null animals show elevated levels of phosphorylated Smad2 after renal injury. The ability to enhance BMP signaling while suppressing TGF-β activation indicates a critical role for KCP in modulating the responses between these anti- and profibrotic cytokines in the initiation and progression of renal interstitial fibrosis.

UR - http://www.scopus.com/inward/record.url?scp=33745024718&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745024718&partnerID=8YFLogxK

U2 - 10.1128/MCB.02127-05

DO - 10.1128/MCB.02127-05

M3 - Article

C2 - 16738323

AN - SCOPUS:33745024718

VL - 26

SP - 4577

EP - 4585

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 12

ER -