Pathway: Erythropoietin activates RAS
Reactions in pathway: Erythropoietin activates RAS :
Erythropoietin activates RAS
The RAS guanine nucleotide exchange factors SOS1 and VAV1 bind indirectly to the phosphorylated EPOR via CRKL, SHC1, and GRB2 (Miura et al. 1994, Hanazono et al. 1996, Odai et al. 1997, Arai et al. 2001, reviewed in Kuhrt et al. 2015) . The phosphorylated cytoplasmic domain of EPOR binds CRKL, which is then phosphorylated (Arai et al. 2001). Phosphorylated CRKL binds SHC1, which is then phosphorylated and binds either GRB2:SOS1 (Barber et al. 1997) or GRB2:VAV1 (Hanazono et al. 1996). SOS1 and phosphorylated VAV1 catalyze the exchange of GDP for GTP bound to RAS, that is, RAS:GDP is converted to RAS:GTP.
Erythropoietin (EPO) is a cytokine that serves as the primary regulator of erythropoiesis, the differentiation of erythrocytes from stem cells in the liver of the fetus and the bone marrow of adult mammals (reviewed in Ingley 2012, Zhang et al. 2014, Kuhrt and Wojchowski 2015). EPO is produced in the kidneys in response to low oxygen tension and binds a receptor, EPOR, located on progenitor cells: burst forming unit-erythroid (BFU-e) cells and colony forming unit-erythroid (CFU-e) cells.
The erythropoietin receptor (EPOR) exists in lipid rafts (reviewed in McGraw and List 2017) as a dimer pre-associated with proteins involved in downstream signaling: the tyrosine kinase JAK2, the tyrosine kinase LYN, and the scaffold protein IRS2. Binding of EPO to the EPOR dimer causes a change in conformation (reviewed in Watowich et al. 2011, Corbett et al. 2016) that activates JAK2, which then transphosphorylates JAK2 and phosphorylates the cytoplasmic domain of EPOR. The phosphorylated EPOR serves directly or indirectly as a docking site for signaling molecules such as STAT5, phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), phospholipase C gamma (PLCG1, PLCG2), and activators of RAS (SHC1, GRB2:SOS1, GRB2:VAV1).
EPO activates 4 major signaling pathways: STAT5-activated transcription, PI3K-AKT, RAS-RAF-ERK, and PLC-PKC. JAK2-STAT5 activates expression of BCL2L1 (Bcl-xL) and therefore appears to be important for anti-apoptosis. PI3K-AKT appears to be important for both anti-apoptosis and proliferation. The roles of other signaling pathways are controversial but both RAS-RAF-MEK-ERK and PLCgamma-PKC have mitogenic effects. Phosphatases such as SHP1 are also recruited and downregulate the EPO signal.
EPO also has effects outside of erythropoiesis. The EPOR is expressed in various tissues such as endothelium where it can act to stimulate growth and promote cell survival (Debeljak et al. 2014, Kimáková et al. 2017). EPO and EPOR in the neurovascular system act via Akt, Wnt1, mTOR, SIRT1, and FOXO proteins to prevent apoptotic cell injury (reviewed in Ostrowski and Heinrich 2018, Maiese 2016) and EPO may have therapeutic value in the nervous system (Ma et al. 2016).
The erythropoietin receptor (EPOR) exists in lipid rafts (reviewed in McGraw and List 2017) as a dimer pre-associated with proteins involved in downstream signaling: the tyrosine kinase JAK2, the tyrosine kinase LYN, and the scaffold protein IRS2. Binding of EPO to the EPOR dimer causes a change in conformation (reviewed in Watowich et al. 2011, Corbett et al. 2016) that activates JAK2, which then transphosphorylates JAK2 and phosphorylates the cytoplasmic domain of EPOR. The phosphorylated EPOR serves directly or indirectly as a docking site for signaling molecules such as STAT5, phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), phospholipase C gamma (PLCG1, PLCG2), and activators of RAS (SHC1, GRB2:SOS1, GRB2:VAV1).
EPO activates 4 major signaling pathways: STAT5-activated transcription, PI3K-AKT, RAS-RAF-ERK, and PLC-PKC. JAK2-STAT5 activates expression of BCL2L1 (Bcl-xL) and therefore appears to be important for anti-apoptosis. PI3K-AKT appears to be important for both anti-apoptosis and proliferation. The roles of other signaling pathways are controversial but both RAS-RAF-MEK-ERK and PLCgamma-PKC have mitogenic effects. Phosphatases such as SHP1 are also recruited and downregulate the EPO signal.
EPO also has effects outside of erythropoiesis. The EPOR is expressed in various tissues such as endothelium where it can act to stimulate growth and promote cell survival (Debeljak et al. 2014, Kimáková et al. 2017). EPO and EPOR in the neurovascular system act via Akt, Wnt1, mTOR, SIRT1, and FOXO proteins to prevent apoptotic cell injury (reviewed in Ostrowski and Heinrich 2018, Maiese 2016) and EPO may have therapeutic value in the nervous system (Ma et al. 2016).
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).