Science 2005,
PMID: 15761148
Ozdamar, Barish; Bose, Rohit; Barrios-Rodiles, Miriam; Wang, Hong-Rui; Zhang, Yue; Wrana, Jeffrey L
The transition of cells from an epithelial to a mesenchymal phenotype is a critical event during morphogenesis in multicellular organisms and underlies the pathology of many diseases, including the invasive phenotype associated with metastatic carcinomas. Transforming growth factor beta (TGFbeta) is a key regulator of epithelial-to-mesenchymal transition (EMT). However, the molecular mechanisms that control the dissolution of tight junctions, an early event in EMT, remain elusive. We demonstrate that Par6, a regulator of epithelial cell polarity and tight-junction assembly, interacts with TGFbeta receptors and is a substrate of the type II receptor, TbetaRII. Phosphorylation of Par6 is required for TGFbeta-dependent EMT in mammary gland epithelial cells and controls the interaction of Par6 with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets the guanosine triphosphatase RhoA for degradation, thereby leading to a loss of tight junctions. These studies define how an extracellular cue signals to the polarity machinery to control epithelial cell morphology.
Document information provided by NCBI PubMed
Text Mining Data
EMT → Par6: "
Phosphorylation of
Par6 is
required for TGFbeta dependent
EMT in mammary gland epithelial cells and controls the interaction of Par6 with the E3 ubiquitin ligase Smurf1
"
Par6 — Smurf1: "
Phosphorylation of Par6 is required for TGFbeta dependent EMT in mammary gland epithelial cells and controls the interaction of Par6 with the E3 ubiquitin ligase Smurf1
"
Manually curated Databases
-
IRef Bind_translation Interaction:
STRAP
—
TGFBR1
(coimmunoprecipitation)
-
IRef Bind_translation Interaction:
FKBP1A
—
TGFBR1
(coimmunoprecipitation)
-
IRef Bind_translation Interaction:
TGFBR1
—
TGFBR1
(coimmunoprecipitation)
-
IRef Biogrid Interaction:
TGFB1
—
PARD6A
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
PARD6A
—
SMURF1
(physical association, affinity chromatography technology)
-
MIPS CORUM TGF-beta-receptor-PAR6 complex:
TGF-beta-receptor-PAR6 complex complex (PARD6A-TGFBR1-TGFBR2)
-
IRef Corum Interaction:
Complex of TGFBR1-TGFBR2-TGFBR2-TGFBR1-PARD6A-PARD6A
(association, luminescence based mammalian interactome mapping)
-
NCI Pathway Database TGF-beta receptor signaling:
TGFB/TGFBR2/TGFBR1/Par6/occludin complex (TGFBR1-PARD6A-OCLN-TGFBR2)
→
betaglycan (dimer) complex (TGFBR3)
(modification, collaborate)
Evidence: assay
-
NCI Pathway Database TGF-beta receptor signaling:
TGFB/TGFBR2/TGFBR1/Par6/occludin complex (TGFBR1-PARD6A-OCLN-TGFBR2)
→
TGFBR1 (dimer)/Par6/occludin complex (TGFBR1-PARD6A-OCLN)
(modification, collaborate)
Evidence: assay
-
NCI Pathway Database TGF-beta receptor signaling:
TGFB/TGFBR2/TGFBR1/Par6/occludin complex (TGFBR1-PARD6A-OCLN-TGFBR2)
→
TGFB/TGFBR2/betaglycan complex (TGFBR3-TGFBR2)
(modification, collaborate)
Evidence: assay
-
NCI Pathway Database TGF-beta receptor signaling:
betaglycan (dimer) complex (TGFBR3)
→
TGFBR1 (dimer)/Par6/occludin complex (TGFBR1-PARD6A-OCLN)
(modification, collaborate)
Evidence: assay
-
NCI Pathway Database TGF-beta receptor signaling:
betaglycan (dimer) complex (TGFBR3)
→
TGFB/TGFBR2/betaglycan complex (TGFBR3-TGFBR2)
(modification, collaborate)
Evidence: assay
-
NCI Pathway Database TGF-beta receptor signaling:
TGFBR1 (dimer)/Par6/occludin complex (TGFBR1-PARD6A-OCLN)
→
TGFB/TGFBR2/betaglycan complex (TGFBR3-TGFBR2)
(modification, collaborate)
Evidence: assay
-
NCI Pathway Database TGF-beta receptor signaling:
RhoA (RHOA)
→
TGFB/TGFBR2/TGFBR1/Par6/occludin/SMURF1 complex (TGFBR1-PARD6A-OCLN-SMURF1-TGFBR2)
(proteasomal ubiquitin-dependent protein catabolic process, collaborate)
Evidence: mutant phenotype
-
NCI Pathway Database TGF-beta receptor signaling:
TGFB/TGFBR2/TGFBR1/Par6/occludin complex (TGFBR1-PARD6A-OCLN-TGFBR2)
→
SMURF1 (SMURF1)
(modification, collaborate)
Evidence: physical interaction
-
NCI Pathway Database TGF-beta receptor signaling:
TGFB/TGFBR2/TGFBR1/Par6/occludin complex (TGFBR1-PARD6A-OCLN-TGFBR2)
→
TGFB/TGFBR2/TGFBR1/Par6/occludin/SMURF1 complex (TGFBR1-PARD6A-OCLN-SMURF1-TGFBR2)
(modification, collaborate)
Evidence: physical interaction
-
NCI Pathway Database TGF-beta receptor signaling:
SMURF1 (SMURF1)
→
TGFB/TGFBR2/TGFBR1/Par6/occludin/SMURF1 complex (TGFBR1-PARD6A-OCLN-SMURF1-TGFBR2)
(modification, collaborate)
Evidence: physical interaction
-
Reactome Reaction:
FKBP1A
→
PRKCZ
(indirect_complex)
-
Reactome Reaction:
TGFB1
→
UBC
(reaction)
-
Reactome Reaction:
RHOA
→
UBC
(indirect_complex)
-
Reactome Reaction:
RHOA
→
UBA52
(indirect_complex)
-
Reactome Reaction:
RHOA
→
UBC
(reaction)
-
Reactome Reaction:
ARHGEF18
→
UBC
(reaction)
-
Reactome Reaction:
RPS27A
→
ARHGEF18
(indirect_complex)
-
Reactome Reaction:
TGFB1
→
PARD6A
(reaction)
-
Reactome Reaction:
PARD6A
→
SMURF1
(indirect_complex)
-
Reactome Reaction:
PRKCZ
→
SMURF1
(reaction)
-
Reactome Reaction:
TGFB1
→
UBA52
(indirect_complex)
-
Reactome Reaction:
TGFBR2
→
UBA52
(reaction)
-
Reactome Reaction:
RHOA
→
UBB
(reaction)
-
Reactome Reaction:
TGFB1
→
TGFBR1
(reaction)
-
Reactome Reaction:
TGFBR2
→
ARHGEF18
(indirect_complex)
-
Reactome Reaction:
FKBP1A
→
TGFBR2
(reaction)
-
Reactome Reaction:
RPS27A
→
SMURF1
(reaction)
-
Reactome Reaction:
RPS27A
→
SMURF1
(indirect_complex)
-
Reactome Reaction:
UBA52
→
PARD6A
(indirect_complex)
-
Reactome Reaction:
TGFB1
→
UBA52
(reaction)
-
Reactome Reaction:
CGN
→
RPS27A
(reaction)
-
Reactome Reaction:
RHOA
→
SMURF1
(indirect_complex)
-
Reactome Reaction:
F11R
→
TGFB1
(indirect_complex)
-
Reactome Reaction:
PARD6A
→
UBB
(indirect_complex)
-
Reactome Reaction:
FKBP1A
→
TGFBR1
(reaction)
-
Reactome Reaction:
RHOA
→
SMURF1
(reaction)
-
Reactome Reaction:
TGFBR2
→
UBB
(indirect_complex)
-
Reactome Reaction:
TGFBR2
→
PARD6A
(indirect_complex)
-
Reactome Reaction:
UBA52
→
PARD3
(indirect_complex)
-
Reactome Reaction:
F11R
→
RPS27A
(indirect_complex)
-
Reactome Reaction:
FKBP1A
→
PARD6A
(reaction)
-
Reactome Reaction:
TGFBR1
→
RPS27A
(reaction)
-
Reactome Reaction:
F11R
→
TGFBR1
(reaction)
-
Reactome Reaction:
RPS27A
→
PARD6A
(reaction)
-
Reactome Reaction:
PRKCZ
→
TGFB1
(reaction)
-
Reactome Reaction:
TGFBR2
→
PARD3
(reaction)
-
Reactome Reaction:
F11R
→
UBA52
(indirect_complex)
-
Reactome Reaction:
UBA52
→
SMURF1
(indirect_complex)
-
Reactome Reaction:
UBA52
→
ARHGEF18
(indirect_complex)
-
Reactome Reaction:
TGFBR2
→
PARD3
(indirect_complex)
-
Reactome Reaction:
UBA52
→
ARHGEF18
(reaction)
-
Reactome Reaction:
RHOA
→
TGFBR1
(indirect_complex)
-
Reactome Reaction:
CGN
→
SMURF1
(indirect_complex)
-
Reactome Reaction:
RPS27A
→
PARD3
(reaction)
-
Reactome Reaction:
CGN
→
FKBP1A
(indirect_complex)
-
Reactome Reaction:
PRKCZ
→
UBB
(reaction)
-
Reactome Reaction:
TGFB1
→
UBB
(indirect_complex)
-
Reactome Reaction:
UBA52
→
PARD6A
(reaction)
-
Reactome Reaction:
FKBP1A
→
RHOA
(reaction)
-
Reactome Reaction:
TGFBR2
→
PARD6A
(reaction)
-
Reactome Reaction:
TGFBR2
→
UBC
(indirect_complex)
-
Reactome Reaction:
RHOA
→
UBA52
(reaction)
-
Reactome Reaction:
UBA52
→
PARD3
(reaction)
-
Reactome Reaction:
TGFB1
→
ARHGEF18
(indirect_complex)
-
Reactome Reaction:
CGN
→
TGFB1
(reaction)
-
Reactome Reaction:
TGFBR1
→
UBA52
(indirect_complex)
-
Reactome Reaction:
TGFBR1
→
PARD6A
(reaction)
-
Reactome Reaction:
F11R
→
TGFBR2
(indirect_complex)
-
Reactome Reaction:
TGFB1
→
SMURF1
(reaction)
-
Reactome Reaction:
TGFBR1
→
PARD3
(indirect_complex)
-
Reactome Reaction:
FKBP1A
→
ARHGEF18
(reaction)
-
Reactome Reaction:
PRKCZ
→
UBA52
(reaction)
-
Reactome Reaction:
RHOA
→
UBB
(indirect_complex)
-
Reactome Reaction:
RPS27A
→
PARD6A
(indirect_complex)
-
Reactome Reaction:
F11R
→
UBB
(indirect_complex)
-
Reactome Reaction:
TGFBR1
→
UBC
(indirect_complex)
-
Reactome Reaction:
F11R
→
TGFBR1
(indirect_complex)
-
Reactome Reaction:
TGFBR2
→
SMURF1
(indirect_complex)
-
Reactome Reaction:
SMURF1
→
UBC
(indirect_complex)
-
Reactome Reaction:
FKBP1A
→
F11R
(reaction)
-
Reactome Reaction:
RHOA
→
TGFB1
(reaction)
-
Reactome Reaction:
CGN
→
UBB
(indirect_complex)
-
Reactome Reaction:
TGFB1
→
PARD3
(reaction)
-
Reactome Reaction:
CGN
→
TGFB1
(indirect_complex)
-
Reactome Reaction:
PRKCZ
→
TGFB1
(indirect_complex)
-
Reactome Reaction:
PRKCZ
→
TGFBR2
(reaction)
-
Reactome Reaction:
TGFBR1
→
ARHGEF18
(reaction)
-
Reactome Reaction:
TGFB1
→
UBB
(reaction)
-
Reactome Reaction:
CGN
→
SMURF1
(reaction)
-
Reactome Reaction:
PRKCZ
→
UBC
(indirect_complex)
-
Reactome Reaction:
CGN
→
UBC
(indirect_complex)
-
Reactome Reaction:
PARD3
→
UBC
(reaction)
-
Reactome Reaction:
F11R
→
RPS27A
(reaction)
-
Reactome Reaction:
FKBP1A
→
ARHGEF18
(indirect_complex)
-
Reactome Reaction:
F11R
→
TGFBR2
(reaction)
-
Reactome Reaction:
RHOA
→
TGFB1
(indirect_complex)
-
Reactome Reaction:
CGN
→
TGFBR1
(reaction)
-
Reactome Reaction:
FKBP1A
→
RHOA
(indirect_complex)
-
Reactome Reaction:
TGFBR1
→
RPS27A
(indirect_complex)
-
Reactome Reaction:
SMURF1
→
UBB
(indirect_complex)
-
Reactome Reaction:
TGFBR1
→
SMURF1
(reaction)
-
Reactome Reaction:
CGN
→
UBB
(reaction)
-
Reactome Reaction:
TGFBR2
→
RPS27A
(indirect_complex)
-
Reactome Reaction:
ARHGEF18
→
SMURF1
(indirect_complex)
-
Reactome Reaction:
PRKCZ
→
RPS27A
(reaction)
-
Reactome Reaction:
SMURF1
→
UBC
(reaction)
-
Reactome Reaction:
SMURF1
→
UBB
(reaction)
-
Reactome Reaction:
RHOA
→
RPS27A
(indirect_complex)
-
Reactome Reaction:
CGN
→
UBC
(reaction)
-
Reactome Reaction:
TGFBR2
→
UBC
(reaction)
-
Reactome Reaction:
FKBP1A
→
PARD6A
(indirect_complex)
-
Reactome Reaction:
TGFBR2
→
UBB
(reaction)
-
Reactome Reaction:
F11R
→
TGFB1
(reaction)
-
Reactome Reaction:
CGN
→
TGFBR1
(indirect_complex)
-
Reactome Reaction:
PRKCZ
→
TGFBR1
(indirect_complex)
-
Reactome Reaction:
TGFBR1
→
UBC
(reaction)
-
Reactome Reaction:
ARHGEF18
→
SMURF1
(reaction)
-
Reactome Reaction:
CGN
→
FKBP1A
(reaction)
-
Reactome Reaction:
ARHGEF18
→
UBC
(indirect_complex)
-
Reactome Reaction:
TGFB1
→
RPS27A
(reaction)
-
Reactome Reaction:
TGFB1
→
SMURF1
(indirect_complex)
-
Reactome Reaction:
TGFB1
→
RPS27A
(indirect_complex)
-
Reactome Reaction:
F11R
→
UBC
(reaction)
-
Reactome Reaction:
TGFBR1
→
PARD3
(reaction)
-
Reactome Reaction:
UBA52
→
SMURF1
(reaction)
-
Reactome Reaction:
PARD3
→
SMURF1
(reaction)
-
Reactome Reaction:
CGN
→
RPS27A
(indirect_complex)
-
Reactome Reaction:
TGFBR1
→
UBB
(reaction)
-
Reactome Reaction:
TGFBR2
→
RPS27A
(reaction)
-
Reactome Reaction:
F11R
→
UBB
(reaction)
-
Reactome Reaction:
FKBP1A
→
PARD3
(indirect_complex)
-
Reactome Reaction:
PARD6A
→
UBB
(reaction)
-
Reactome Reaction:
PRKCZ
→
TGFBR1
(reaction)
-
Reactome Reaction:
CGN
→
TGFBR2
(indirect_complex)
-
Reactome Reaction:
PRKCZ
→
RPS27A
(indirect_complex)
-
Reactome Reaction:
TGFB1
→
PARD6A
(indirect_complex)
-
Reactome Reaction:
RPS27A
→
PARD3
(indirect_complex)
-
Reactome Reaction:
TGFBR1
→
PARD6A
(indirect_complex)
-
Reactome Reaction:
TGFBR1
→
UBA52
(reaction)
-
Reactome Reaction:
TGFBR1
→
SMURF1
(indirect_complex)
-
Reactome Reaction:
F11R
→
SMURF1
(reaction)
-
Reactome Reaction:
FKBP1A
→
TGFB1
(reaction)
-
Reactome Reaction:
FKBP1A
→
F11R
(indirect_complex)
-
Reactome Reaction:
RHOA
→
TGFBR2
(reaction)
-
Reactome Reaction:
TGFB1
→
UBC
(indirect_complex)
-
Reactome Reaction:
PARD3
→
SMURF1
(indirect_complex)
-
Reactome Reaction:
TGFB1
→
ARHGEF18
(reaction)
-
Reactome Reaction:
RHOA
→
TGFBR1
(reaction)
-
Reactome Reaction:
PARD6A
→
UBC
(indirect_complex)
-
Reactome Reaction:
F11R
→
UBC
(indirect_complex)
-
Reactome Reaction:
TGFB1
→
PARD3
(indirect_complex)
-
Reactome Reaction:
ARHGEF18
→
UBB
(reaction)
-
Reactome Reaction:
TGFBR2
→
SMURF1
(reaction)
-
Reactome Reaction:
PARD6A
→
SMURF1
(reaction)
-
Reactome Reaction:
PARD3
→
UBB
(reaction)
-
Reactome Reaction:
RPS27A
→
ARHGEF18
(reaction)
-
Reactome Reaction:
CGN
→
TGFBR2
(reaction)
-
Reactome Reaction:
TGFBR1
→
ARHGEF18
(indirect_complex)
-
Reactome Reaction:
CGN
→
UBA52
(indirect_complex)
-
Reactome Reaction:
TGFBR1
→
UBB
(indirect_complex)
-
Reactome Reaction:
ARHGEF18
→
UBB
(indirect_complex)
-
Reactome Reaction:
PRKCZ
→
TGFBR2
(indirect_complex)
-
Reactome Reaction:
TGFBR2
→
ARHGEF18
(reaction)
-
Reactome Reaction:
PRKCZ
→
UBC
(reaction)
-
Reactome Reaction:
PARD3
→
UBC
(indirect_complex)
-
Reactome Reaction:
F11R
→
UBA52
(reaction)
-
Reactome Reaction:
PRKCZ
→
SMURF1
(indirect_complex)
-
Reactome Reaction:
CGN
→
UBA52
(reaction)
-
Reactome Reaction:
TGFBR1
→
TGFBR2
(reaction)
-
Reactome Reaction:
RHOA
→
TGFBR2
(indirect_complex)
-
Reactome Reaction:
PRKCZ
→
UBA52
(indirect_complex)
-
Reactome Reaction:
PARD6A
→
UBC
(reaction)
-
Reactome Reaction:
RHOA
→
RPS27A
(reaction)
-
Reactome Reaction:
F11R
→
SMURF1
(indirect_complex)
-
Reactome Reaction:
PARD3
→
UBB
(indirect_complex)
-
Reactome Reaction:
PRKCZ
→
UBB
(indirect_complex)
-
Reactome Reaction:
TGFBR2
→
UBA52
(indirect_complex)
-
Reactome Reaction:
FKBP1A
→
PRKCZ
(reaction)
-
Reactome Reaction:
FKBP1A
→
PARD3
(reaction)
In total, 104 gene pairs are associated to this article in curated databases