Signal Transduction

Stable Identifier
Homo sapiens
Signaling Pathways
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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).

Literature References
PubMed ID Title Journal Year
19935667 Fine-tuning of GPCR activity by receptor-interacting proteins

Hall, RA, Ritter, SL

Nat Rev Mol Cell Biol 2009
21252999 Feedback regulation of EGFR signalling: decision making by early and delayed loops

Yarden, Y, Avraham, R

Nat Rev Mol Cell Biol 2011
19619488 Wnt/beta-catenin signaling: components, mechanisms, and diseases

MacDonald, BT, Tamai, K, He, X

Dev Cell 2009
17496910 Integrating signals from RTKs to ERK/MAPK

McKay, MM, Morrison, DK

Oncogene 2007
18043707 Heterotrimeric G protein activation by G-protein-coupled receptors

Oldham, WM, Hamm, HE

Nat Rev Mol Cell Biol 2008
21781017 Regulation of small GTPases at epithelial cell-cell junctions

Citi, S, Schneider, Y, Spadaro, D, Pulimeno, P, Stutz, J

Mol Membr Biol 2011
17604717 AKT/PKB signaling: navigating downstream

Manning, BD, Cantley, LC

Cell 2007
15520807 The RAF proteins take centre stage

Wellbrock, C, Karasarides, M, Marais, R

Nat Rev Mol Cell Biol 2004
11742412 Insulin signalling and the regulation of glucose and lipid metabolism

Saltiel, AR, Kahn, CR

Nature 2001
19379690 The canonical Notch signaling pathway: unfolding the activation mechanism

Kopan, R, Ilagan, MXG

Cell 2009
15863030 Cellular signaling by fibroblast growth factor receptors

Schlessinger, J, Eswarakumar, VP, Lax, I

Cytokine Growth Factor Rev 2005
15450248 Constitutive and inducible expression and regulation of vascular endothelial growth factor

Shi, Q, Wei, D, Xie, K, Huang, S

Cytokine Growth Factor Rev 2004
17084981 Signalling via integrins: implications for cell survival and anticancer strategies

Cordes, N, Haase, M, Hehlgans, S

Biochim Biophys Acta 2007
18483217 Role of platelet-derived growth factors in physiology and medicine

Betsholtz, C, Andrae, J, Gallini, R

Genes Dev 2008
19762341 Bone morphogenetic protein receptors and signal transduction

Miyazono, K, Kamiya, Y, Morikawa, M

J Biochem 2010
19458711 The structure and function of G-protein-coupled receptors

Rasmussen, SG, Rosenbaum, DM, Kobilka, BK

Nature 2009
16939974 Neurotrophin-regulated signalling pathways

Reichardt, LF

Philos Trans R Soc Lond B Biol Sci 2006
19648010 New regulatory mechanisms of TGF-beta receptor function

Kang, JS, Derynck, R, Liu, C

Trends Cell Biol 2009
19536106 Proximal events in Wnt signal transduction

Angers, S, Moon, RT

Nat Rev Mol Cell Biol 2009
16260143 Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling

Snyder, SH, Nikolaidis, N, van Rossum, DB, Gill, DL, Patterson, RL

Trends Biochem Sci 2005
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