Pathway: TGF-beta receptor signaling activates SMADs
Reactions in pathway: TGF-beta receptor signaling activates SMADs :
TGF-beta receptor signaling activates SMADs
Binding of transforming growth factor beta 1 (TGF beta 1, i.e. TGFB1) to TGF beta receptor type 2 (TGFBR2) activates TGF beta receptor signaling cascade. TGFB1 is posttranslationally processed by furin (Dubois et al. 1995) to form a homodimer and secreted to the extracellular space as part of the large latent complex (LLC). After the LLC disassembles in the extracellular space, dimeric TGFB1 becomes capable of binding to TGFBR2 (Annes et al. 2003, Keski Oja et al. 2004). Formation of TGFB1:TGFBR2 complex creates a binding pocket for TGF-beta receptor type-1 (TGFBR1) and TGFBR1 is recruited to the complex by binding to both TGFB1 and TGFBR2. This results in an active heterotetrameric TGF-beta receptor complex that consists of TGFB1 homodimer bound to two heterodimers of TGFBR1 and TGFBR2 (Wrana et al. 1992, Moustakas et al. 1993, Franzen et al. 1993). TGF-beta signaling can also occur through a single heterodimer of TGFBR1 and TGFBR2, although with decreased efficiency (Huang et al. 2011). TGFBR1 and TGFBR2 interact through their extracellular domains, which brings their cytoplasmic domains together. Ligand binding to extracellular receptor domains is cooperative, but no conformational change is seen from crystal structures of either TGFB1- or TGFB3-bound heterotetrameric receptor complexes (Groppe et al. 2008, Radaev et al. 2010).
Activation of TGFBR1 by TGFBR2 in the absence of ligand is prevented by FKBP1A (FKBP12), a peptidyl-prolyl cis-trans isomerase. FKBP1A forms a complex with inactive TGFBR1 and dissociates from it only after TGFBR1 is recruited by TGFB1-bound TGFBR2 (Chen et al. 1997).
Both TGFBR1 and TGFBR2 are receptor serine/threonine kinases. Formation of the hetero-tetrameric TGF-beta receptor complex (TGFBR) in response to TGFB1 binding induces receptor rotation, so that TGFBR2 and TGFBR1 cytoplasmic kinase domains face each other in a catalytically favourable configuration. TGFBR2 trans-phosphorylates serine residues at the conserved Gly-Ser-rich juxtapositioned domain (GS domain) of TGFBR1 (Wrana et al. 1994, Souchelnytskyi et al. 1996), activating TGFBR1.
In addition to phosphorylation, TGFBR1 may also be sumoylated in response to TGF-beta stimulation. Sumoylation enhances TGFBR1 kinase activity (Kang et al. 2008).
The activated TGFBR complex is internalized by clathrin-mediated endocytosis into early endosomes. With the assistance of SARA, an early endosome membrane protein, phosphorylated TGFBR1 within TGFBR complex recruits SMAD2 and/or SMAD3 , i.e. R-SMADs (Tsukazaki et al. 1998). TGFBR1 phosphorylates recruited SMAD2/3 on two C-terminal serine residues (Souchelnytskyi et al. 2001). The phosphorylation changes the conformation of SMAD2/3 MH2 domain, promoting dissociation of SMAD2/3 from SARA and TGFBR1 (Souchelnytskyi et al. 1997, Macias-Silva et al. 1996, Nakao et al. 1997) and formation of SMAD2/3 trimers (Chacko et al. 2004). The phosphorylated C-terminal tail of SMAD2/3 has high affinity for SMAD4 (Co-SMAD), inducing formation of SMAD2/3:SMAD4 heterotrimers, composed of two phosphorylated R-SMADs (SMAD2 and/or SMAD3) and SMAD4 (Co-SMAD). SMAD2/3:SMAD4 heterotrimers are energetically favored over R-SMAD trimers (Nakao et al. 1997, Qin et al. 2001, Kawabata et al. 1998, Chacko et al. 2004).
SMAD2/3:SMAD4 heterotrimers translocate to the nucleus where they act as transcriptional regulators.
Activation of TGFBR1 by TGFBR2 in the absence of ligand is prevented by FKBP1A (FKBP12), a peptidyl-prolyl cis-trans isomerase. FKBP1A forms a complex with inactive TGFBR1 and dissociates from it only after TGFBR1 is recruited by TGFB1-bound TGFBR2 (Chen et al. 1997).
Both TGFBR1 and TGFBR2 are receptor serine/threonine kinases. Formation of the hetero-tetrameric TGF-beta receptor complex (TGFBR) in response to TGFB1 binding induces receptor rotation, so that TGFBR2 and TGFBR1 cytoplasmic kinase domains face each other in a catalytically favourable configuration. TGFBR2 trans-phosphorylates serine residues at the conserved Gly-Ser-rich juxtapositioned domain (GS domain) of TGFBR1 (Wrana et al. 1994, Souchelnytskyi et al. 1996), activating TGFBR1.
In addition to phosphorylation, TGFBR1 may also be sumoylated in response to TGF-beta stimulation. Sumoylation enhances TGFBR1 kinase activity (Kang et al. 2008).
The activated TGFBR complex is internalized by clathrin-mediated endocytosis into early endosomes. With the assistance of SARA, an early endosome membrane protein, phosphorylated TGFBR1 within TGFBR complex recruits SMAD2 and/or SMAD3 , i.e. R-SMADs (Tsukazaki et al. 1998). TGFBR1 phosphorylates recruited SMAD2/3 on two C-terminal serine residues (Souchelnytskyi et al. 2001). The phosphorylation changes the conformation of SMAD2/3 MH2 domain, promoting dissociation of SMAD2/3 from SARA and TGFBR1 (Souchelnytskyi et al. 1997, Macias-Silva et al. 1996, Nakao et al. 1997) and formation of SMAD2/3 trimers (Chacko et al. 2004). The phosphorylated C-terminal tail of SMAD2/3 has high affinity for SMAD4 (Co-SMAD), inducing formation of SMAD2/3:SMAD4 heterotrimers, composed of two phosphorylated R-SMADs (SMAD2 and/or SMAD3) and SMAD4 (Co-SMAD). SMAD2/3:SMAD4 heterotrimers are energetically favored over R-SMAD trimers (Nakao et al. 1997, Qin et al. 2001, Kawabata et al. 1998, Chacko et al. 2004).
SMAD2/3:SMAD4 heterotrimers translocate to the nucleus where they act as transcriptional regulators.
The human genome encodes 33 TGF-beta family members, including TGF-beta itself, as well as bone morphogenetic protein (BMP), activin, nodal and growth and differentiation factors (GDFs). This superfamily of ligands generally binds as dimers to hetero-tetrameric cell-surface receptor serine/threonine kinases to activate SMAD-dependent and SMAD-independent signaling (reviewed in Morikawa et al, 2016; Budi et al, 2017).
Signaling by the TGF-beta receptor complex is initiated by TGF-beta. TGF-beta (TGFB1), secreted as a homodimer, binds to TGF-beta receptor II (TGFBR2), inducing its dimerization and formation of a stable hetero-tetrameric complex with TGF-beta receptor I homodimer (TGFBR1). TGFBR2-mediated phosphorylation of TGFBR1 triggers internalization of the heterotetrameric TGF beta receptor complex (TGFBR) into clathrin coated endocytic vesicles and recruitment of cytosolic SMAD2 and SMAD3, which act as R-SMADs for TGF beta receptor complex. TGFBR1 phosphorylates SMAD2 and SMAD3, promoting their association with SMAD4 (known as Co-SMAD). In the nucleus, the SMAD2/3:SMAD4 heterotrimer binds target DNA elements and, in cooperation with other transcription factors, regulates expression of genes involved in cell differentiation. For a review of TGF-beta receptor signaling, please refer to Kang et al. 2009.
Signaling by BMP is triggered by bone morphogenetic proteins (BMPs). BMPs can bind type I receptors in the absence of type II receptors, but the presence of both types dramatically increases binding affinity. The type II receptor kinase transphosphorylates the type I receptor, leading to recruitment and phosphorylation of SMAD1, SMAD5 and SMAD8, which function as R-SMADs in BMP signalling pathways. Phosphorylated SMAD1, SMAD5 and SMAD8 form heterotrimeric complexes with SMAD4, the only Co-SMAD in mammals. The SMAD1/5/8:SMAD4 heterotrimer regulates transcription of genes involved in development of many tissues, including bone, cartilage, blood vessels, heart, kidney, neurons, liver and lung. For review of BMP signaling, please refer to Miyazono et al. 2010.
Signaling by activin is triggered when an activin dimer (activin A, activin AB or activin B) binds the type II receptor (ACVR2A, ACVR2B). This complex then interacts with the type I receptor (ACVR1B, ACVR1C) and phosphorylates it. The phosphorylated type I receptor phosphorylates SMAD2 and SMAD3. Dimers of phosphorylated SMAD2/3 bind SMAD4 and the resulting ternary complex enters the nucleus and activates target genes. For a review of activin signaling, please refer to Chen et al. 2006.
Signaling by the TGF-beta receptor complex is initiated by TGF-beta. TGF-beta (TGFB1), secreted as a homodimer, binds to TGF-beta receptor II (TGFBR2), inducing its dimerization and formation of a stable hetero-tetrameric complex with TGF-beta receptor I homodimer (TGFBR1). TGFBR2-mediated phosphorylation of TGFBR1 triggers internalization of the heterotetrameric TGF beta receptor complex (TGFBR) into clathrin coated endocytic vesicles and recruitment of cytosolic SMAD2 and SMAD3, which act as R-SMADs for TGF beta receptor complex. TGFBR1 phosphorylates SMAD2 and SMAD3, promoting their association with SMAD4 (known as Co-SMAD). In the nucleus, the SMAD2/3:SMAD4 heterotrimer binds target DNA elements and, in cooperation with other transcription factors, regulates expression of genes involved in cell differentiation. For a review of TGF-beta receptor signaling, please refer to Kang et al. 2009.
Signaling by BMP is triggered by bone morphogenetic proteins (BMPs). BMPs can bind type I receptors in the absence of type II receptors, but the presence of both types dramatically increases binding affinity. The type II receptor kinase transphosphorylates the type I receptor, leading to recruitment and phosphorylation of SMAD1, SMAD5 and SMAD8, which function as R-SMADs in BMP signalling pathways. Phosphorylated SMAD1, SMAD5 and SMAD8 form heterotrimeric complexes with SMAD4, the only Co-SMAD in mammals. The SMAD1/5/8:SMAD4 heterotrimer regulates transcription of genes involved in development of many tissues, including bone, cartilage, blood vessels, heart, kidney, neurons, liver and lung. For review of BMP signaling, please refer to Miyazono et al. 2010.
Signaling by activin is triggered when an activin dimer (activin A, activin AB or activin B) binds the type II receptor (ACVR2A, ACVR2B). This complex then interacts with the type I receptor (ACVR1B, ACVR1C) and phosphorylates it. The phosphorylated type I receptor phosphorylates SMAD2 and SMAD3. Dimers of phosphorylated SMAD2/3 bind SMAD4 and the resulting ternary complex enters the nucleus and activates target genes. For a review of activin signaling, please refer to Chen et al. 2006.
Signal transduction is a process in which extracellular signals elicit changes in cell state and activity. Transmembrane receptors sense changes in the cellular environment by binding ligands, such as hormones and growth factors, or reacting to other types of stimuli, such as light. Stimulation of transmembrane receptors leads to their conformational change which propagates the signal to the intracellular environment by activating downstream signaling cascades. Depending on the cellular context, this may impact cellular proliferation, differentiation, and survival. On the organism level, signal transduction regulates overall growth and behavior.
Receptor tyrosine kinases (RTKs) transmit extracellular signals by phosphorylating their protein partners on conserved tyrosine residues. Some of the best studied RTKs are EGFR (reviewed in Avraham and Yarden, 2011), FGFR (reviewed in Eswarakumar et al, 2005), insulin receptor (reviewed in Saltiel and Kahn, 2001), NGF (reviewed in Reichardt, 2006), PDGF (reviewed in Andrae et al, 2008) and VEGF (reviewed in Xie et al, 2004). RTKs frequently activate downstream signaling through RAF/MAP kinases (reviewed in McKay and Morrison, 2007 and Wellbrock et al 2004), AKT (reviewed in Manning and Cantley, 2007) and PLC- gamma (reviewed in Patterson et al, 2005), which ultimately results in changes in gene expression and cellular metabolism.
Receptor serine/threonine kinases of the TGF-beta family, such as TGF-beta receptors (reviewed in Kang et al. 2009) and BMP receptors (reviewed in Miyazono et al. 2009), transmit extracellular signals by phosphorylating regulatory SMAD proteins on conserved serine and threonine residues. This leads to formation of complexes of regulatory SMADs and SMAD4, which translocate to the nucleus where they act as transcription factors.
WNT receptors transmit their signal through beta-catenin. In the absence of ligand, beta-catenin is constitutively degraded in a ubiquitin-dependent manner. WNT receptor stimulation releases beta-catenin from the destruction complex, allowing it to translocate to the nucleus where it acts as a transcriptional regulator (reviewed in MacDonald et al, 2009 and Angers and Moon, 2009). WNT receptors were originally classified as G-protein coupled receptors (GPCRs). Although they are structurally related, GPCRs primarily transmit their signals through G-proteins, which are trimers of alpha, beta and gamma subunits. When a GPCR is activated, it acts as a guanine nucleotide exchange factor, catalyzing GDP to GTP exchange on the G-alpha subunit of the G protein and its dissociation from the gamma-beta heterodimer. The G-alpha subunit regulates the activity of adenylate cyclase, while the gamma-beta heterodimer can activate AKT and PLC signaling (reviewed in Rosenbaum et al. 2009, Oldham and Hamm 2008, Ritter and Hall 2009).
NOTCH receptors are activated by transmembrane ligands expressed on neighboring cells, which results in cleavage of NOTCH receptor and release of its intracellular domain. NOTCH intracellular domain translocates to the nucleus where it acts as a transcription factor (reviewed in Kopan and Ilagan, 2009).
Integrins are activated by extracellular matrix components, such as fibronectin and collagen, leading to conformational change and clustering of integrins on the cell surface. This results in activation of integrin-linked kinase and other cytosolic kinases and, in co-operation with RTK signaling, regulates survival, proliferation and cell shape and adhesion (reviewed in Hehlgans et al, 2007) .
Besides inducing changes in gene expression and cellular metabolism, extracellular signals that trigger the activation of Rho GTP-ases can trigger changes in the organization of cytoskeleton, thereby regulating cell polarity and cell-cell junctions (reviewed in Citi et al, 2011).
Receptor tyrosine kinases (RTKs) transmit extracellular signals by phosphorylating their protein partners on conserved tyrosine residues. Some of the best studied RTKs are EGFR (reviewed in Avraham and Yarden, 2011), FGFR (reviewed in Eswarakumar et al, 2005), insulin receptor (reviewed in Saltiel and Kahn, 2001), NGF (reviewed in Reichardt, 2006), PDGF (reviewed in Andrae et al, 2008) and VEGF (reviewed in Xie et al, 2004). RTKs frequently activate downstream signaling through RAF/MAP kinases (reviewed in McKay and Morrison, 2007 and Wellbrock et al 2004), AKT (reviewed in Manning and Cantley, 2007) and PLC- gamma (reviewed in Patterson et al, 2005), which ultimately results in changes in gene expression and cellular metabolism.
Receptor serine/threonine kinases of the TGF-beta family, such as TGF-beta receptors (reviewed in Kang et al. 2009) and BMP receptors (reviewed in Miyazono et al. 2009), transmit extracellular signals by phosphorylating regulatory SMAD proteins on conserved serine and threonine residues. This leads to formation of complexes of regulatory SMADs and SMAD4, which translocate to the nucleus where they act as transcription factors.
WNT receptors transmit their signal through beta-catenin. In the absence of ligand, beta-catenin is constitutively degraded in a ubiquitin-dependent manner. WNT receptor stimulation releases beta-catenin from the destruction complex, allowing it to translocate to the nucleus where it acts as a transcriptional regulator (reviewed in MacDonald et al, 2009 and Angers and Moon, 2009). WNT receptors were originally classified as G-protein coupled receptors (GPCRs). Although they are structurally related, GPCRs primarily transmit their signals through G-proteins, which are trimers of alpha, beta and gamma subunits. When a GPCR is activated, it acts as a guanine nucleotide exchange factor, catalyzing GDP to GTP exchange on the G-alpha subunit of the G protein and its dissociation from the gamma-beta heterodimer. The G-alpha subunit regulates the activity of adenylate cyclase, while the gamma-beta heterodimer can activate AKT and PLC signaling (reviewed in Rosenbaum et al. 2009, Oldham and Hamm 2008, Ritter and Hall 2009).
NOTCH receptors are activated by transmembrane ligands expressed on neighboring cells, which results in cleavage of NOTCH receptor and release of its intracellular domain. NOTCH intracellular domain translocates to the nucleus where it acts as a transcription factor (reviewed in Kopan and Ilagan, 2009).
Integrins are activated by extracellular matrix components, such as fibronectin and collagen, leading to conformational change and clustering of integrins on the cell surface. This results in activation of integrin-linked kinase and other cytosolic kinases and, in co-operation with RTK signaling, regulates survival, proliferation and cell shape and adhesion (reviewed in Hehlgans et al, 2007) .
Besides inducing changes in gene expression and cellular metabolism, extracellular signals that trigger the activation of Rho GTP-ases can trigger changes in the organization of cytoskeleton, thereby regulating cell polarity and cell-cell junctions (reviewed in Citi et al, 2011).