Pathway: TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition)
Reactions in pathway: TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) :
TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition)
In normal cells and in the early stages of cancer development, signaling by TGF-beta plays a tumor suppressive role, as SMAD2/3:SMAD4-mediated transcription inhibits cell division by downregulating MYC oncogene transcription and stimulating transcription of CDKN2B tumor suppressor gene. In advanced cancers however, TGF-beta signaling promotes metastasis by stimulating epithelial to mesenchymal transition (EMT).
TGFBR1 is recruited to tight junctions by binding PARD6A, a component of tight junctions. After TGF-beta stimulation, activated TGFBR2 binds TGFBR1 at tight junctions, and phosphorylates both TGFBR1 and PARD6A. Phosphorylated PARD6A recruits SMURF1 to tight junctions. SMURF1 is able to ubiquitinate RHOA, a component of tight junctions needed for tight junction maintenance, leading to disassembly of tight junctions, an important step in EMT (Wang et al. 2003, Ozdamar et al. 2005).
TGFBR1 is recruited to tight junctions by binding PARD6A, a component of tight junctions. After TGF-beta stimulation, activated TGFBR2 binds TGFBR1 at tight junctions, and phosphorylates both TGFBR1 and PARD6A. Phosphorylated PARD6A recruits SMURF1 to tight junctions. SMURF1 is able to ubiquitinate RHOA, a component of tight junctions needed for tight junction maintenance, leading to disassembly of tight junctions, an important step in EMT (Wang et al. 2003, Ozdamar et al. 2005).
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).