Signaling by TGF-beta Receptor Complex (Homo sapiens)
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Description
The TGF-beta/BMP pathway incorporates several signaling pathways that share most, but not all, components of a central signal transduction engine. The general signaling scheme is rather simple: upon binding of a ligand, an activated plasma membrane receptor complex is formed, which passes on the signal towards the nucleus through a phosphorylated receptor SMAD (R-SMAD). In the nucleus, the activated R-SMAD promotes transcription in complex with a closely related helper molecule termed Co-SMAD (SMAD4). However, this simple linear pathway expands into a network when various regulatory components and mechanisms are taken into account. The signaling pathway includes a great variety of different TGF-beta/BMP superfamily ligands and receptors, several types of the R-SMADs, and functionally critical negative feedback loops. The R-SMAD:Co-SMAD complex can interact with a great number of transcriptional co-activators/co-repressors to regulate positively or negatively effector genes, so that the interpretation of a signal depends on the cell-type and cross talk with other signaling pathways such as Notch, MAPK and Wnt. The pathway plays a number of different biological roles in the control of embryonic and adult cell proliferation and differentiation, and it is implicated in a great number of human diseases.
TGF beta (TGFB1) is secreted as a homodimer, and as such it binds to TGF beta receptor II (TGFBR2), inducing its dimerization. Binding of TGF beta enables TGFBR2 to form a stable hetero-tetrameric complex with TGF beta receptor I homodimer (TGFBR1). TGFBR2 acts as a serine/threonine kinase and phosphorylates serine and threonine residues within the short GS domain (glycine-serine rich domain) of TGFBR1.
The phosphorylated heterotetrameric TGF beta receptor complex (TGFBR) internalizes into clathrin coated endocytic vesicles where it associates with the endosomal membrane protein SARA. SARA facilitates the recruitment of cytosolic SMAD2 and SMAD3, which act as R-SMADs for TGF beta receptor complex. TGFBR1 phosphorylates recruited SMAD2 and SMAD3, inducing a conformational change that promotes formation of R-SMAD trimers and dissociation of R-SMADs from the TGF beta receptor complex.
In the cytosol, phosphorylated SMAD2 and SMAD3 associate with SMAD4 (known as Co-SMAD), forming a heterotrimer which is more stable than the R-SMAD homotrimers. R-SMAD:Co-SMAD heterotrimer translocates to the nucleus where it directly binds DNA and, in cooperation with other transcription factors, regulates expression of genes involved in cell differentiation, in a context-dependent manner.
The intracellular level of SMAD2 and SMAD3 is regulated by SMURF ubiquitin ligases, which target R-SMADs for degradation. In addition, nuclear R-SMAD:Co-SMAD heterotrimer stimulates transcription of inhibitory SMADs (I-SMADs), forming a negative feedback loop. I-SMADs bind the phosphorylated TGF beta receptor complexes on caveolin coated vesicles, derived from the lipid rafts, and recruit SMURF ubiquitin ligases to TGF beta receptors, leading to ubiquitination and degradation of TGFBR1. Nuclear R-SMAD:Co-SMAD heterotrimers are targets of nuclear ubiquitin ligases which ubiquitinate SMAD2/3 and SMAD4, causing heterotrimer dissociation, translocation of ubiquitinated SMADs to the cytosol and their proteasome-mediated degradation. For a recent review of TGF-beta receptor signaling, please refer to Kang et al. 2009. View original pathway at Reactome.
TGF beta (TGFB1) is secreted as a homodimer, and as such it binds to TGF beta receptor II (TGFBR2), inducing its dimerization. Binding of TGF beta enables TGFBR2 to form a stable hetero-tetrameric complex with TGF beta receptor I homodimer (TGFBR1). TGFBR2 acts as a serine/threonine kinase and phosphorylates serine and threonine residues within the short GS domain (glycine-serine rich domain) of TGFBR1.
The phosphorylated heterotetrameric TGF beta receptor complex (TGFBR) internalizes into clathrin coated endocytic vesicles where it associates with the endosomal membrane protein SARA. SARA facilitates the recruitment of cytosolic SMAD2 and SMAD3, which act as R-SMADs for TGF beta receptor complex. TGFBR1 phosphorylates recruited SMAD2 and SMAD3, inducing a conformational change that promotes formation of R-SMAD trimers and dissociation of R-SMADs from the TGF beta receptor complex.
In the cytosol, phosphorylated SMAD2 and SMAD3 associate with SMAD4 (known as Co-SMAD), forming a heterotrimer which is more stable than the R-SMAD homotrimers. R-SMAD:Co-SMAD heterotrimer translocates to the nucleus where it directly binds DNA and, in cooperation with other transcription factors, regulates expression of genes involved in cell differentiation, in a context-dependent manner.
The intracellular level of SMAD2 and SMAD3 is regulated by SMURF ubiquitin ligases, which target R-SMADs for degradation. In addition, nuclear R-SMAD:Co-SMAD heterotrimer stimulates transcription of inhibitory SMADs (I-SMADs), forming a negative feedback loop. I-SMADs bind the phosphorylated TGF beta receptor complexes on caveolin coated vesicles, derived from the lipid rafts, and recruit SMURF ubiquitin ligases to TGF beta receptors, leading to ubiquitination and degradation of TGFBR1. Nuclear R-SMAD:Co-SMAD heterotrimers are targets of nuclear ubiquitin ligases which ubiquitinate SMAD2/3 and SMAD4, causing heterotrimer dissociation, translocation of ubiquitinated SMADs to the cytosol and their proteasome-mediated degradation. For a recent review of TGF-beta receptor signaling, please refer to Kang et al. 2009. View original pathway at Reactome.
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DataNodes
p-TGFBR1: BAMBI:
SMAD7Junction
Complex:TGFB1:TGFBR2:TGFBR1:PARD6A:RHOAJunction
Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA:SMURF1Junction
Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOAJunction
Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:Ub-RHOA:SMURF1Junction
Complex:TGFBR1:PARD6A:RHOAactivity of SMAD2/SMAD3:SMAD4
heterotrimerAnnotated Interactions
In addition to phosphorylation, TGFBR1 may also be sumoylated in response to TGF-beta-1 stimulation. Sumoylation enhances TGFBR1 function by facilitating recruitment and phosphorylation of SMAD3 (Kang et al. 2008).
ZFYVE16 (endofin) promotes SMAD heterotrimer formation. ZFYVE16 can bind TGFBR1 and facilitate SMAD2 phosphorylation, and it can also bind SMAD4, but the exact mechanism of ZFYVE16 (endofin) action in the context of TGF-beta receptor signaling is not known (Chen et al. 2007).
PARD6A, bound to PARD3 and PRKCZ, is associated with tight junctions through JAM-A (Ebnet et al. 2001), which is bound to CGN (cingulin) (Bazzoni et al. 2000). CGN binds ARHGEF18 (p114RhoGEF), and ARHGEF18 recruits RHOA to tight junctions. Other components of the tight junction structure are not shown in this context (Terry et al. 2011).
Junctional RHOA activity is required for maintenance of junctional integrity through regulation of actinomyosin cytoskeleton organization (Terry et al. 2011). This was inferred from experiments in which a recombinant mouse Pard6a and recombinant human TGFBR1 were studied in the context of endogenous mouse tight junctions.
p-TGFBR1: BAMBI:
SMAD7Junction
Complex:TGFB1:TGFBR2:TGFBR1:PARD6A:RHOAJunction
Complex:TGFB1:TGFBR2:TGFBR1:PARD6A:RHOAJunction
Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA:SMURF1Junction
Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA:SMURF1Junction
Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOAJunction
Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOAJunction
Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:Ub-RHOA:SMURF1Junction
Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:Ub-RHOA:SMURF1Junction
Complex:TGFBR1:PARD6A:RHOAJunction
Complex:TGFBR1:PARD6A:RHOA