TGF-beta Signaling Pathways

Interactive Pathways

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LAP
LAP
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Latent TGF-beta
Latent TGF-beta
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TGF-beta Dimer
TGF-beta Dimer
TGF-beta RI
TGF-beta RI
TGF-beta RII
TGF-beta RII
TGF-beta RIII or Endoglin
TGF-beta RIII or Endoglin
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Daxx
Daxx
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JNK
JNK
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PAK2
PAK2
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p38
p38
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PP2A
PP2A
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p70 S6K
p70 S6K
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ROCK
ROCK
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PI 3-K
PI 3-K
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PDK-1
PDK-1
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Akt
Akt
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TOR
TOR
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Shc
Shc
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GRB2
GRB2
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SOS
SOS
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Ras
Ras
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Raf
Raf
MEK1/2
MEK1/2
ERK1/2
ERK1/2
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TRAF-6
TRAF-6
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TAK1
TAK1
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MKK3/6
MKK3/6
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p38
p38
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MKK4
MKK4
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JNK
JNK
Smad1/5/8
Smad1/5/8
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Smad4
Smad4
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Smad1/5/8
Smad1/5/8
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Smad2/3
Smad2/3
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Smad4
Smad4
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Smad2/3
Smad2/3
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Smurf1/2
Smurf1/2
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Smad7
Smad7
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Smad2/3 or Smad1/5/8
Smad2/3 or Smad1/5/8
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Smad4
Smad4
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Smad2/3 or Smad1/5/8
Smad2/3 or Smad1/5/8
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Smad4
Smad4
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CoA,
CoR
CoA,
CoR
DNA-binding Transcription Factor
DNA-binding Transcription Factor

Cleavage/ICD Nuclear Translocation

Cleavage/ICD Nuclear Translocation

Degradation

Degradation

Target Genes
Target Genes
Chromatin Remodeling Factors
Chromatin Remodeling Factors
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Smurf1
Smurf1
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RhoA
RhoA
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Cdc42 or Rac1
Cdc42 or Rac1
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RhoA
RhoA
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Par6
Par6
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SARA
SARA
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Overview of TGF-beta Signaling

TGF-beta proteins are highly pleiotropic cytokines that regulate a diverse range of processes during development and adult tissue homeostasis, including cell proliferation, apoptosis, autophagy, inflammation, angiogenesis, and epithelial-to-mesenchymal transition. TGF-beta molecules are normally secreted as part of an inactive, latent complex that consists of an N-terminal latency-associated peptide (LAP) and a C-terminal mature TGF-beta monomer. Disulfide-linked homodimers of LAP and TGF-beta remain noncovalently associated after secretion, forming the small latent TGF-beta complex. Covalent linkage of LAP to one of three latent TGF-beta binding proteins (LTBPs) creates a large latent complex that may interact with the extracellular matrix. Activation of TGF-beta is controlled both spatially and temporally by the actions of proteases or select integrins.

TGF-beta signals through a heterotetrameric receptor complex composed of two type I and two type II transmembrane receptor subunits with serine/threonine kinase domains. Following ligand binding, the type II receptor (TGF-beta RII) phosphorylates the type I receptor (TGF-beta RI), leading to recruitment and phosphorylation of Smad2 and Smad3 in most cell types. Alternatively, Smad1 and Smad5 can be activated by TGF-beta signaling in some cell types depending on the type I receptor that is expressed. Activated Smad proteins associate with Smad4 and translocate to the nucleus, where they recruit additional transcriptional regulators, including DNA-binding transcription factors, co-activators, co-repressors, and chromatin remodeling factors, that control the expression of numerous target genes. Differential expression of these factors may be responsible for some of the cell type-specific responses to TGF-beta. Accessory proteins such as soluble or membrane-bound regulators or co-receptors can also affect TGF-beta signaling. In addition, TGF-beta can activate a number of Smad-independent signaling pathways, including Ras/MAPK, PI 3-K/Akt, p38, JNK, and RhoA/ROCK in a cell type-specific and context-dependent manner. Activation of these pathways may also contribute to the cellular responses induced by TGF-beta.

To learn more, please visit our TGF-beta Superfamily Research Area.