PathwayStep4155 Signaling by EGFR DAG and IP3 signaling Signaling by FGFR RAF/MAP kinase cascade PIP3 activates AKT signaling PathwayStep5118 PathwayStep5248 PathwayStep5275 PathwayStep5285 PathwayStep5367 PathwayStep5323 PathwayStep5487 PathwayStep5441 PathwayStep5418 PathwayStep5425 PathwayStep5558 PathwayStep5831 PathwayStep5845 PathwayStep5918 PathwayStep5929 PathwayStep5939 PathwayStep5876 PathwayStep3927 Signaling by Activin Signaling by Wnt Integrin cell surface interactions Signaling by Hippo Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) Signaling by NGF Signaling by PDGF Signaling by VEGF Signaling by SCF-KIT Signaling by ERBB2 Signaling by ERBB4 Signaling by Rho GTPases Signaling by TGF-beta Receptor Complex Signaling by BMP Signaling by NOTCH Signaling by GPCR Signaling Pathways Authored: Bevan, AP, Charalambous, M, Gopinathrao, G, Joshi-Tope, G, Rothfels, K, Orlic-Milacic, Marija, 2005--0-5- Pubmed11742412 Pubmed15450248 Pubmed15520807 Pubmed15863030 Pubmed16260143 Pubmed16939974 Pubmed17084981 Pubmed17496910 Pubmed17604717 Pubmed18043707 Pubmed18483217 Pubmed19379690 Pubmed19458711 Pubmed19536106 Pubmed19619488 Pubmed19648010 Pubmed19762341 Pubmed19935667 Pubmed21252999 Pubmed21781017 Reactome Database ID Release 43162582 Reactome, http://www.reactome.org ReactomeREACT_111102 Reviewed: Barroso, I, Stanley, FM, Joutel, A, Rush, MG, 0000-00-00 00:00:00 Signal Transduction 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), 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). Signaling by Insulin receptor PathwayStep3897 PathwayStep3857 PathwayStep3841