signal transduction


Summary: The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.

Top Publications

  1. Fraguas S, Barberán S, Iglesias M, Rodríguez Esteban G, Cebria F. egr-4, a target of EGFR signaling, is required for the formation of the brain primordia and head regeneration in planarians. Development. 2014;141:1835-47 pubmed publisher
  2. Ali F, Cheng K, Kirwan P, Metcalfe S, Livesey F, Barker R, et al. The phosphorylation status of Ascl1 is a key determinant of neuronal differentiation and maturation in vivo and in vitro. Development. 2014;141:2216-24 pubmed publisher
  3. Kichev A, Rousset C, Baburamani A, Levison S, Wood T, Gressens P, et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling and cell death in the immature central nervous system after hypoxia-ischemia and inflammation. J Biol Chem. 2014;289:9430-9 pubmed publisher
    ..The toxicity of TRAIL in primary neurons suggests that TRAIL signaling participates in neonatal brain injury after inflammation and HI. ..
  4. O Hayre M, Degese M, Gutkind J. Novel insights into G protein and G protein-coupled receptor signaling in cancer. Curr Opin Cell Biol. 2014;27:126-35 pubmed publisher
    ..Understanding GPCR involvement in cancer malignancy may help identify novel therapeutic opportunities for cancer prevention and treatment. ..
  5. Khatri S, Edlund R, Groves A. Foxi3 is necessary for the induction of the chick otic placode in response to FGF signaling. Dev Biol. 2014;391:158-69 pubmed publisher
    ..The early expression but late requirement for Foxi3 in ear induction suggests it may have some of the properties associated with pioneer transcription factors...
  6. Varelas X. The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease. Development. 2014;141:1614-26 pubmed publisher
    ..Here, I provide an overview of these and other regulatory mechanisms and outline important developmental processes controlled by TAZ and YAP. ..
  7. Berndsen C, Wolberger C. New insights into ubiquitin E3 ligase mechanism. Nat Struct Mol Biol. 2014;21:301-7 pubmed publisher
    ..Only recently have the catalytic mechanisms of E3 ligases begun to be elucidated. ..
  8. Cai X, Chen J, Xu H, Liu S, Jiang Q, Halfmann R, et al. Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell. 2014;156:1207-1222 pubmed publisher
    ..These results indicate that prion-like polymerization is a conserved signal transduction mechanism in innate immunity and inflammation.
  9. Zahreddine H, Culjkovic Kraljacic B, Assouline S, Gendron P, Romeo A, Morris S, et al. The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation. Nature. 2014;511:90-3 pubmed publisher
    ..Resistance is overcome by genetic or pharmacological inhibition of GLI1, revealing a potential strategy to overcome drug resistance in some patients. ..

More Information


  1. Justilien V, Walsh M, Ali S, Thompson E, Murray N, Fields A. The PRKCI and SOX2 oncogenes are coamplified and cooperate to activate Hedgehog signaling in lung squamous cell carcinoma. Cancer Cell. 2014;25:139-51 pubmed publisher
    ..Thus, PKC? and SOX2 are genetically, biochemically, and functionally linked in LSCC, and together they drive tumorigenesis by establishing a cell-autonomous Hh signaling axis. ..
  2. Lohse M, Maiellaro I, Calebiro D. Kinetics and mechanism of G protein-coupled receptor activation. Curr Opin Cell Biol. 2014;27:87-93 pubmed publisher
  3. O Reilly S, Ciechomska M, Cant R, van Laar J. Interleukin-6 (IL-6) trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-? (TGF-?) signaling promoting SMAD3 activation and fibrosis via Gremlin protein. J Biol Chem. 2014;289:9952-60 pubmed publisher
    ..This is due to induction of the bone morphogenetic protein (BMP) antagonist Gremlin-1, and we show that Gremlin-1 is profibrotic and is mediated through canonical TGF-? signaling. ..
  4. Saint Jeannet J, Moody S. Establishing the pre-placodal region and breaking it into placodes with distinct identities. Dev Biol. 2014;389:13-27 pubmed publisher
    ..In this review we summarize recent advances in the characterization of the signaling molecules and transcriptional effectors that regulate PPR specification and its subdivision into placodal domains with distinct identities. ..
  5. Del Re D, Matsuda T, Zhai P, Maejima Y, Jain M, Liu T, et al. Mst1 promotes cardiac myocyte apoptosis through phosphorylation and inhibition of Bcl-xL. Mol Cell. 2014;54:639-50 pubmed publisher
    ..Our findings demonstrate mitochondrial localization of Hippo signaling and identify Bcl-xL as a target that is directly modified to promote apoptosis. ..
  6. Demetriades C, Doumpas N, Teleman A. Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2. Cell. 2014;156:786-99 pubmed publisher
    ..These data suggest that regulation of TSC2 subcellular localization may be a general mechanism to control its activity and place TSC2 in the amino-acid-sensing pathway to TORC1...
  7. Wisler J, Xiao K, Thomsen A, Lefkowitz R. Recent developments in biased agonism. Curr Opin Cell Biol. 2014;27:18-24 pubmed publisher
    ..Here we review recent major developments in these areas over the past several years. ..
  8. Jaumouillé V, Farkash Y, Jaqaman K, Das R, Lowell C, Grinstein S. Actin cytoskeleton reorganization by Syk regulates Fc? receptor responsiveness by increasing its lateral mobility and clustering. Dev Cell. 2014;29:534-546 pubmed publisher
  9. Winograd Katz S, Fassler R, Geiger B, Legate K. The integrin adhesome: from genes and proteins to human disease. Nat Rev Mol Cell Biol. 2014;15:273-88 pubmed publisher
  10. Puisieux A, Brabletz T, Caramel J. Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol. 2014;16:488-94 pubmed publisher
  11. Yimlamai D, Christodoulou C, Galli G, Yanger K, Pepe Mooney B, Gurung B, et al. Hippo pathway activity influences liver cell fate. Cell. 2014;157:1324-38 pubmed publisher
  12. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178-96 pubmed publisher
    ..Among these, transforming growth factor-? (TGF?) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT. ..
  13. Furukawa Y, Teraguchi S, Ikegami T, Dagliyan O, Jin L, Hall D, et al. Intrinsic disorder mediates cooperative signal transduction in STIM1. J Mol Biol. 2014;426:2082-97 pubmed publisher
    Intrinsically disordered domains have been reported to play important roles in signal transduction networks by introducing cooperativity into protein-protein interactions...
  14. Edlund R, Ohyama T, Kantarci H, Riley B, Groves A. Foxi transcription factors promote pharyngeal arch development by regulating formation of FGF signaling centers. Dev Biol. 2014;390:1-13 pubmed publisher
    ..Our results suggest that Foxi3 may play a role in the establishment of signaling centers in the branchial arches that are required for neural crest survival, patterning and the subsequent development of branchial arch derivatives. ..
  15. Sun C, Wang L, Huang S, Heynen G, Prahallad A, Robert C, et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature. 2014;508:118-22 pubmed publisher
  16. Morioka S, Broglie P, Omori E, Ikeda Y, Takaesu G, Matsumoto K, et al. TAK1 kinase switches cell fate from apoptosis to necrosis following TNF stimulation. J Cell Biol. 2014;204:607-23 pubmed publisher
    ..Our results reveal that TAK1 activation drives RIPK3-dependent necrosis and inhibits apoptosis. TAK1 acts as a switch between apoptosis and necrosis. ..
  17. Lobry C, Oh P, Mansour M, Look A, Aifantis I. Notch signaling: switching an oncogene to a tumor suppressor. Blood. 2014;123:2451-9 pubmed publisher
    ..In this review, we summarize and discuss latest advances in the understanding of this dual role in hematopoiesis and the possible consequences for the treatment of hematologic malignancies. ..
  18. Wang H, Sun L, Su L, Rizo J, Liu L, Wang L, et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol Cell. 2014;54:133-146 pubmed publisher
    ..This property allows MLKL to move from the cytosol to the plasma and intracellular membranes, where it directly disrupts membrane integrity, resulting in necrotic death. ..
  19. Li D, Sakuma R, Vakili N, Mo R, Puviindran V, Deimling S, et al. Formation of proximal and anterior limb skeleton requires early function of Irx3 and Irx5 and is negatively regulated by Shh signaling. Dev Cell. 2014;29:233-40 pubmed publisher
    ..Our data provide genetic evidence supporting the concept of early specification and progressive determination of anterior limb pattern. ..
  20. Ngo Q, Vogler H, Lituiev D, Nestorova A, Grossniklaus U. A calcium dialog mediated by the FERONIA signal transduction pathway controls plant sperm delivery. Dev Cell. 2014;29:491-500 pubmed publisher
    ..Thus, complex intercellular interactions involving a receptor kinase pathway and calcium-mediated signaling control sperm delivery in plants...
  21. Principe D, Doll J, Bauer J, Jung B, Munshi H, Bartholin L, et al. TGF-?: duality of function between tumor prevention and carcinogenesis. J Natl Cancer Inst. 2014;106:djt369 pubmed publisher
    ..Understanding the mechanisms of TGF-? dysregulation will likely reveal novel points of convergence between TGF-? and other pathways that can be specifically targeted for therapy. ..
  22. Holmström K, Finkel T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol. 2014;15:411-21 pubmed publisher
    ..on cells and invading microorganisms, are increasingly implicated in various cell fate decisions and signal transduction pathways...
  23. Yee C, Yang W, Hekimi S. The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C. elegans. Cell. 2014;157:897-909 pubmed publisher
    ..This results in extended longevity when mtROS generation is inappropriately elevated. These findings clarify the relationships between mitochondria, ROS, apoptosis, and aging...
  24. Schaeffer V, Akutsu M, Olma M, Gomes L, Kawasaki M, Dikic I. Binding of OTULIN to the PUB domain of HOIP controls NF-?B signaling. Mol Cell. 2014;54:349-61 pubmed publisher
    ..Functionally, HOIP binding to OTULIN is required for the recruitment of OTULIN to the TNF receptor complex and to counteract HOIP-dependent activation of the NF-?B pathway. ..
  25. Cheng J, Blum R, Bowman C, Hu D, Shilatifard A, Shen S, et al. A role for H3K4 monomethylation in gene repression and partitioning of chromatin readers. Mol Cell. 2014;53:979-92 pubmed publisher
    ..Our findings point to a unique role for H3K4 monomethylation in establishing boundaries that restrict the recruitment of chromatin-modifying enzymes to defined regions within promoters. ..
  26. Muller P, Vousden K. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell. 2014;25:304-17 pubmed publisher
    ..Understanding the functions of mutant p53 will help in the development of new therapeutic approaches that may be useful in a broad range of cancer types. ..
  27. Nihira K, Miki Y, Ono K, Suzuki T, Sasano H. An inhibition of p62/SQSTM1 caused autophagic cell death of several human carcinoma cells. Cancer Sci. 2014;105:568-75 pubmed publisher
    p62/SQSTM1 (p62) is a multifunctional protein implicated in several signal transduction pathways and selectively degraded by autophagy, a process for lysosomal degradation of both protein and organelle...
  28. Klip A, Sun Y, Chiu T, Foley K. Signal transduction meets vesicle traffic: the software and hardware of GLUT4 translocation. Am J Physiol Cell Physiol. 2014;306:C879-86 pubmed publisher
    ..Using the analogy of an integrated circuit to approach the intersection between signal transduction and vesicle mobilization, we identify signaling relays ("software") that engage structural/mechanical ..
  29. Khoo K, Hoe K, Verma C, Lane D. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov. 2014;13:217-36 pubmed publisher
    ..The challenge of targeting protein-protein interactions and a fragile mutant transcription factor has stimulated many exciting new approaches to drug discovery. ..
  30. Silvestre M, Viollet B, Caton P, Leclerc J, Sakakibara I, Foretz M, et al. The AMPK-SIRT signaling network regulates glucose tolerance under calorie restriction conditions. Life Sci. 2014;100:55-60 pubmed publisher
    ..5-fold vs. control, *p<0.05). This study demonstrates that skeletal muscle-specific AMPK deficiency impairs the beneficial effects of CR on glucose tolerance and that these effects may be dependent on reduced SIRT1 levels. ..
  31. Seguin L, Kato S, Franovic A, Camargo M, Lesperance J, Elliott K, et al. An integrin β₃-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nat Cell Biol. 2014;16:457-68 pubmed publisher
    ..These findings not only identify α(v)β₃ as a marker/driver of carcinoma stemness but also reveal a therapeutic strategy to sensitize such tumours to RTK inhibition. ..
  32. Riddiford N, Schlosser G. Six1 and Eya1 both promote and arrest neuronal differentiation by activating multiple Notch pathway genes. Dev Biol. 2017;431:152-167 pubmed publisher
  33. Oh S, Kim J, Kim Y, Lee M, Kook M, Choi E, et al. The extracellular matrix protein Edil3 stimulates osteoblast differentiation through the integrin ?5?1/ERK/Runx2 pathway. PLoS ONE. 2017;12:e0188749 pubmed publisher
    ..Taken together, these results suggest that Edil3 may stimulate osteoblast differentiation and matrix mineralization by increasing expression of Runx2 through ?5?1 integrin /ERK pathway. ..
  34. Fayngerts S, Wang Z, Zamani A, Sun H, Boggs A, Porturas T, et al. Direction of leukocyte polarization and migration by the phosphoinositide-transfer protein TIPE2. Nat Immunol. 2017;18:1353-1360 pubmed publisher
    ..Thus, the leukocyte polarizer is a dual-role phosphoinositide-transfer protein and represents a potential therapeutic target for the treatment of inflammatory diseases. ..
  35. Wu B, Li Y, Ong K, Sun Y, Shrestha S, Hou L, et al. Reduction of In-Stent Restenosis by Cholesteryl Ester Transfer Protein Inhibition. Arterioscler Thromb Vasc Biol. 2017;37:2333-2341 pubmed publisher
  36. Loviglio M, Arbogast T, Jønch A, Collins S, Popadin K, Bonnet C, et al. The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs. Am J Hum Genet. 2017;101:564-577 pubmed publisher
    ..Taken together, our results suggest that LAT, besides its well-recognized function in T cell development, is a major contributor of the 16p11.2 220 kb BP2-BP3 CNV-associated neurodevelopmental phenotypes. ..
  37. Shao J, Yin Y, Yin X, Ji L, Xin Y, Zou J, et al. Transthyretin Exerts Pro-Apoptotic Effects in Human Retinal Microvascular Endothelial Cells Through a GRP78-Dependent Pathway in Diabetic Retinopathy. Cell Physiol Biochem. 2017;43:788-800 pubmed publisher
    ..In the DR environment (hyperglycemia and hypoxia), TTR was shown to repress neovascularization by promoting apoptosis of hRECs through a GRP78-dependent pathway. ..
  38. Schwarz Y, Zhao N, Kirchhoff F, Bruns D. Astrocytes control synaptic strength by two distinct v-SNARE-dependent release pathways. Nat Neurosci. 2017;20:1529-1539 pubmed publisher
  39. Wei S, Shen X, Gong Z, Deng Y, Lai L, Liang H. FSHR and LHR Expression and Signaling as Well as Maturation and Apoptosis of Cumulus-Oocyte Complexes Following Treatment with FSH Receptor Binding Inhibitor in Sheep. Cell Physiol Biochem. 2017;43:660-669 pubmed publisher
    ..Our study will help to therapy effectively ovarian diseases, improve ovarian and follicular functions, and further to promote fertility of humans and animals. ..
  40. Ponsero A, Igbaria A, Darch M, Miled S, Outten C, Winther J, et al. Endoplasmic Reticulum Transport of Glutathione by Sec61 Is Regulated by Ero1 and Bip. Mol Cell. 2017;67:962-973.e5 pubmed publisher
    ..Thus, the ER redox poise is tuned by reciprocal control of glutathione import and Ero1 activation. The ER protein-conducting channel is permeable to small molecules, provided the driving force of a concentration gradient. ..
  41. Wu X, Zhang L, Toombs J, Kuo Y, Piazza J, Tuladhar R, et al. Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumour suppressor. Nat Cell Biol. 2017;19:1226-1236 pubmed publisher
    ..Our findings delineate a chemical strategy for countering drug resistance in GLI-associated tumours and reveal unanticipated functions for BCL-2 proteins as transcriptional regulators. ..
  42. Zhang D, Qiu W, Jin P, Wang P, Sun Y. Role of autophagy and its molecular mechanisms in mice intestinal tract after severe burn. J Trauma Acute Care Surg. 2017;83:716-724 pubmed publisher
    ..The AMPK/mTOR pathway may involve in the activation of burn-induced autophagy. Therapeutic/care management, levels of evidence are not applicable to some studies, such as in vitro work, animal models, cadaver studies. ..
  43. Sung J, Na K, Kim H. Down-regulation of Inositol Polyphosphate 4-Phosphatase Type II Expression in Colorectal Carcinoma. Anticancer Res. 2017;37:5525-5531 pubmed
    ..Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates phosphatidylinositol 3-kinase signaling and has a tumor-suppressive role in several human malignancies...
  44. Matson J, Livny J, DiRita V. A putative Vibrio cholerae two-component system controls a conserved periplasmic protein in response to the antimicrobial peptide polymyxin B. PLoS ONE. 2017;12:e0186199 pubmed publisher
    ..cholerae to sense and respond to envelope stress...
  45. Agarwal R, Narayan J, Bhattacharyya A, Saraswat M, Tomar A. Gene expression profiling, pathway analysis and subtype classification reveal molecular heterogeneity in hepatocellular carcinoma and suggest subtype specific therapeutic targets. Cancer Genet. 2017;216-217:37-51 pubmed publisher
    ..Conclusively, this study has exposed a number of interesting genes which can be exploited in future as potential markers of HCC, diagnostic as well as prognostic and subtype classification may guide for improved and specific therapy...
  46. Hara K, Hamada C, Wakabayashi K, Kanda R, Kaneko K, Horikoshi S, et al. Scavenging of reactive oxygen species by astaxanthin inhibits epithelial-mesenchymal transition in high glucose-stimulated mesothelial cells. PLoS ONE. 2017;12:e0184332 pubmed publisher
    ..AST may be an efficacious treatment for PF. ..
  47. Gao H, He F, Lin X, Wu Y. Drosophila VAMP7 regulates Wingless intracellular trafficking. PLoS ONE. 2017;12:e0186938 pubmed publisher
    ..We hypothesize that VAMP7 is required for Wg intracellular trafficking and the accumulation of Wg in Rab4-dependent recycling endosomes might affect Wg signaling. ..
  48. Chen Y, Granger A, Tran T, Saulnier J, Kirkwood A, Sabatini B. Endogenous G?q-Coupled Neuromodulator Receptors Activate Protein Kinase A. Neuron. 2017;96:1070-1083.e5 pubmed publisher
    ..Thus, these results highlight PKA as a biochemical integrator of three major types of GPCRs and necessitate reconsideration of classic models used to predict neuronal signaling in response to the large family of G?q-coupled receptors. ..
  49. Kandhaya Pillai R, Miro Mur F, Alijotas Reig J, Tchkonia T, Kirkland J, Schwartz S. TNFα-senescence initiates a STAT-dependent positive feedback loop, leading to a sustained interferon signature, DNA damage, and cytokine secretion. Aging (Albany NY). 2017;9:2411-2435 pubmed publisher
    ..Our findings suggest a positive feedback mechanism via the STAT pathway that sustains cytokine production and reveal a reciprocal regulatory role of JAK/STAT in TNFα-mediated senescence. ..
  50. Ren Z, Chen S, Qing T, Xuan J, Couch L, Yu D, et al. Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017;392:11-21 pubmed publisher
    ..In summary, our data indicate that both ER stress and the activation of JNK and ERK1/2 contribute to leflunomide-induced cytotoxicity. ..
  51. Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, et al. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity. 2017;47:566-581.e9 pubmed publisher
    ..Our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia. ..
  52. Wu G, Luo J, Li H, Huang C, Chang C. Robust gdf9 and bmp15 expression in the oocytes of ovotestes through the Figla-independent pathway in the hermaphroditic black porgy, Acanthopagrus schlegelii. PLoS ONE. 2017;12:e0186991 pubmed publisher
    ..This functional switch might clarify how oocytes created an appropriate microenvironment during the transition from the ancient gonochorism to the present hermaphroditism. ..
  53. Essig K, Hu D, Guimaraes J, Alterauge D, Edelmann S, Raj T, et al. Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells. Immunity. 2017;47:1067-1082.e12 pubmed publisher
    ..Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells. ..