TGF-beta Signaling Pathway (Homo sapiens)

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PP1PPP2APCNF-kBjunctionspathwayCofilinGene expression of tightTGF beta Signaling PathwayCYERK dependentDissolutionNURASMAP2K3TERTMAPK1NUP214WWP1PIK3R2TGIF1BCAR1PJA1SNW1ZFYVE16E2F4ATF3TRAF6ROCK1RUNX2TRAP1CDKN2BRAF1COL1A2SKP1TGFB1MAPK14MAPK3ZFYVE9FOSBATF2CCND1RBL1RBX1SMAD2BTRCPDK1SMAD4SPTBN1CDKN1ARNF111MAPK1SMURF1TGFB1S6KMAPK9UBE2ISKICOPS5KLF11ITGB1METFN1FOXH1TGFBR3PPM1AMAPK14THBS1RNF111SHC1YAP1JUNBCUL1MAPK3PIK3R1ETS1SMAD7RAC1MAP4K1SIN3AE2F5KLF10TGFB1I1SMAD4WWP1SMURF1APPRBL2CAV1DAB2SKP1MAP2K2SNIP1PIAS1NUP214MAPK8SP1MYCCDC42TGFBR2SMAD7MAP2K4NEDD9UCHL5TFDP1SMAD7MMP12CDK1HDAC1DCP1ABTRCTGFBR2TNCITGA2TGFB1SMAD3RBX1KLF6CREBBPCITED1MYCFOSSTAMBPL1SMAD7GRB2MEF2CNUP153TAB1LIMK2FOXP3MAPK8PRKAR2AMMP1SMAD7MAPK9JUNPTK2PMLSMURF2TGFBR1SKILNUP153SMAD4ZEB2RHOAPARD6ATP53HGSCCNB2ZEB1MAP2K1SUMO1AKT1TGFBR1JUNDSOS1SIK1EP300SRCSTRAPPAK2ITGB4MTORITCHSMAD2COPS5SMURF1EID2MAP2K6SMURF2MEF2AMAP3K7NEDD4LKLF10CUL1PIAS2TGFBR3AXIN1ITGB3SMAD3PPPPPPPPPPPPPPPPPPProteinProteinmRNALigandReceptorProteinProtein - protein dissociationEnzyme ComplexSmall moleculeInduced activationInhibitionAuto catalysisTransportPositive regulation of gene expressionLeads to through unknown mechanismNegative regulation of gene expressionTranslocation UbiquitinationDeubiquitinationSumoylationInduced catalysisProtein-protein interactionAcetylationDephosphorylationLEGENDPhosphorylationDeacetylationGolgi apparatusEndosomeNucleusMitochondrionDesumoylationMethylationDemethylationPalmitoylationCytoplasmECPlasma membraneMTEndoplasmic reticulumCYPMGONUExtracellularERENProteolytic cleavageMoleculePCYNUCYNUCYNUCYNUCYNUCYNUCYNUCYNUCYNUCYNU


Description

The signal transduction mechanisms underlying the pathophysiological activities of transforming growth factor-β (TGF-β) have been extensively studied since its discovery nearly 30 years ago. TGF-β ligands belong to a large superfamily of cytokines that bears its name (TGF-β Superfamily) and includes bone morphogenic proteins, activins, inhibin, growth/differentiation factors, Mullerian inhibiting substance, Nodal, and several other structurally-related polypeptides. Mammals express three TGF-β isoforms (i.e., TGF-β1, TGF-β2, and TGF-β3) that are encoded by distinct genes in a tissue-specific and developmentally-regulated manner. TGF-β was identified originally via its stimulation of morphological transformation and anchorage-independent growth in fibroblasts; however, this cytokine is now recognized as being a potent tumor suppressor that prevents the dysregulated growth and survival of epithelial, endothelial, and hematopoietic cells. In addition, numerous studies have clearly established TGF-β as a multifunctional cytokine that plays essential roles in regulating virtually all aspects of mammalian development and differentiation, and in maintaining mammalian tissue homeostasis. The pleiotropic nature of TGF-β is highlighted by the fact that every cell in the metazoan body can produce and respond to this cytokine. Even more remarkably, malignant cells have evolved a variety of complex mechanisms capable of circumventing the tumor suppressing activities of TGF-β, and in doing so, typically convert the functions of TGF-β to that of a tumor promoter, particularly the induction of carcinoma epithelial-mesenchymal transition, invasion, and dissemination to distant organ sites. This peculiar conversion in TGF-β function is known as the "TGF-β Paradox", which underlies the lethality of TGF-β in metastatic cancer cells. Thus, elucidating the effectors and signaling modules activated by TGF-β may offer new insights into the development of novel neoadjuvants capable of effectively targeting the TGF-β pathway to significantly improve the clinical course of patients with cancer, fibrosis, or immunologic disorders. TGF-β is secreted from cells as a latent homodimeric polypeptide that becomes tethered to the extracellular matrix by latent-TGF-β-binding proteins. Mature TGF-β isoforms are activated and liberated from extracellular matrix depots by a variety of mechanisms, including proteolysis, reactive oxygen species, changes in pH, and physical interactions with integrins, thromobspondin-1, or SPARC. Once activated, mature TGF-β initiates transmembrane signaling by binding to two distinct transmembrane Ser/Thr protein kinases, termed TGF-β type I (TβR-I) and type II (TβR-II) receptors. In some cells and tissues, TGF-β also binds to a third cell surface receptor, TGF-β type III (TβR-III), which transfers TGF-β to TβR-II and TβR-I. Full activation of these cytokine:receptor ternary complexes transpires upon TβR-II-mediated transphosphorylation and activation of TβR-I, which then phosphorylates and activates the latent transcription factors, Smad2 and Smad3. Afterward, phosphorylated Smad2/3 interact physically with Smad4, with the resulting heterotrimers translocating into the nucleus to regulate the expression of TGF-β-responsive genes. These Smad-dependent events are subject to fine-tuning and crosstalk regulation in the cytoplasm by their interaction with a variety of adapter molecules, including SARA, Hgs, PML and Dab2, and with Smad7, whose inhibitory activity is modulated by STRAP, AMSH2, and Arkadia; and in the nucleus by their interaction with a variety of transcriptional activators and repressors that occur in a gene- and cell-specific manner. In addition to activating canonical Smad2/3-dependent signaling, accumulating evidence clearly links the development of a variety of human pathologies to aberrant coupling of TGF-β to its noncanonical effector molecules. Included in this ever expanding list of noncanonical signaling molecules stimulated by TGF-β are PI3K, AKT, mTOR, integrins and focal adhesion kinase, and members of the MAP kinase (e.g., ERK1/2, JNK, and p38 MAPK small GTP-binding proteins (e.g., Ras, Rho, and Rac1). The interactions and intersections between canonical and noncanonical TGF-β signaling systems are depicted in the pathway map.

Please access this pathway at NetSlim database. If you use this pathway, you must cite following paper:

Kandasamy, K., Mohan, S. S., Raju, R., Keerthikumar, S., Kumar, G. S. S., Venugopal, A. K., Telikicherla, D., Navarro, J. D., Mathivanan, S., Pecquet, C., Gollapudi, S. K., Tattikota, S. G., Mohan, S., Padhukasahasram, H., Subbannayya, Y., Goel, R., Jacob, H. K. C., Zhong, J., Sekhar, R., Nanjappa, V., Balakrishnan, L., Subbaiah, R., Ramachandra, Y. L., Rahiman, B. A., Prasad, T. S. K., Lin, J., Houtman, J. C. D., Desiderio, S., Renauld, J., Constantinescu, S. N., Ohara, O., Hirano, T., Kubo, M., Singh, S., Khatri, P., Draghici, S., Bader, G. D., Sander, C., Leonard, W. J. and Pandey, A. (2010). NetPath: A public resource of curated signal transduction pathways. Genome Biology. 11:R3

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History

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CompareRevisionActionTimeUserComment
90028view19:37, 8 October 2016AlexanderPicoModified description
87408view11:09, 22 July 2016MkutmonModified description
87394view11:05, 22 July 2016MaintBotadded missing graphids
86819view18:55, 11 July 2016KhanspersQuick edit to datanode annotation or property
84196view23:15, 28 January 2016KhanspersRemoved redundant legend
84195view23:11, 28 January 2016KhanspersRemoved redundant legend and random extra arc
83869view00:52, 18 December 2015AlexanderPicoModified title
79966view15:00, 28 April 2015Zariannotated COL1A2
79341view13:12, 21 March 2015EgonwRandom change to trigger update to the GPML 2013a schema.
79340view13:08, 21 March 2015EgonwReverted to version '04:16, 17 April 2013' by Egonw
69026view17:49, 8 July 2013MaintBotUpdated to 2013 gpml schema
61702view04:16, 17 April 2013MaintBotfixed missing xrefs
61682view21:49, 16 April 2013MaintBotfixed xrefs
61678view21:41, 16 April 2013MaintBot
47976view14:31, 23 April 2012NetPathModified description
45152view01:34, 7 October 2011AlexanderPicofixed db ref
45088view20:58, 6 October 2011KhanspersOntology Term : 'transforming growth factor-beta superfamily mediated signaling pathway' added !
44604view21:19, 21 September 2011KhanspersUpdating content to NetSlim
44119view20:49, 24 August 2011KhanspersReverted to version '23:44, 1 March 2011' by Khanspers
44048view23:45, 22 August 2011KhanspersModified description
44047view23:43, 22 August 2011KhanspersUpdating pathway from NetSlim
41205view23:44, 1 March 2011MaintBotRemoved redundant pathway information and comments
35302view23:29, 11 February 2010NsalomonisModified description
35301view23:26, 11 February 2010NsalomonisModified description
21445view11:31, 14 November 2008MaintBot[[Pathway:Homo sapiens:TGF-beta-Receptor NetPath 7]] moved to [[Pathway:WP366]]: Moved to stable identifier
8434view13:46, 7 January 2008MaintBot[[Pathway:Human:TGF-beta-Receptor NetPath 7]] moved to [[Pathway:Homo sapiens:TGF-beta-Receptor NetPath 7]]: Renaming species
7833view16:21, 18 December 2007MaintBotfixed category names
7304view12:42, 4 November 2007MaintBotAdded categories to GPML
6397view22:18, 22 May 2007A.Pandeygpml file for [[Human:TGF-beta-Receptor_NetPath_7]]

External references

DataNodes

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NameTypeDatabase referenceComment
AKT1Protein207 (Entrez Gene)
APPProtein351 (Entrez Gene)
ATF2Protein1386 (Entrez Gene)
ATF3Protein467 (Entrez Gene)
AXIN1Protein8312 (Entrez Gene)
BCAR1Protein9564 (Entrez Gene)
BTRCProtein8945 (Entrez Gene)
CAV1Protein857 (Entrez Gene)
CCNB2Protein9133 (Entrez Gene)
CCND1Protein595 (Entrez Gene)
CDC42Protein998 (Entrez Gene)
CDK1Protein983 (Entrez Gene)
CDKN1AProtein1026 (Entrez Gene)
CDKN2BProtein1030 (Entrez Gene)
CITED1Protein4435 (Entrez Gene)
COL1A2Protein1278 (Entrez Gene)
COPS5Protein10987 (Entrez Gene)
CREBBPProtein1387 (Entrez Gene)
CUL1Protein8454 (Entrez Gene)
DAB2Protein1601 (Entrez Gene)
DCP1AProtein55802 (Entrez Gene)
E2F4Protein1874 (Entrez Gene)
E2F5Protein1875 (Entrez Gene)
EID2Protein163126 (Entrez Gene)
EP300Protein2033 (Entrez Gene)
ETS1Protein2113 (Entrez Gene)
FN1Protein2335 (Entrez Gene)
FOSProtein2353 (Entrez Gene)
FOSBProtein2354 (Entrez Gene)
FOXH1Protein8928 (Entrez Gene)
FOXP3Protein50943 (Entrez Gene)
GRB2Protein2885 (Entrez Gene)
HDAC1Protein3065 (Entrez Gene)
HGSProtein9146 (Entrez Gene)
ITCHProtein83737 (Entrez Gene)
ITGA2Protein3673 (Entrez Gene)
ITGB1Protein3688 (Entrez Gene)
ITGB3Protein3690 (Entrez Gene)
ITGB4Protein3691 (Entrez Gene)
JUNProtein3725 (Entrez Gene)
JUNBProtein3726 (Entrez Gene)
JUNDProtein3727 (Entrez Gene)
KLF10Protein7071 (Entrez Gene)
KLF11Protein8462 (Entrez Gene)
KLF6Protein1316 (Entrez Gene)
LIMK2Protein3985 (Entrez Gene)
MAP2K1Protein5604 (Entrez Gene)
MAP2K2Protein5605 (Entrez Gene)
MAP2K3Protein5606 (Entrez Gene)
MAP2K4Protein6416 (Entrez Gene)
MAP2K6Protein5608 (Entrez Gene)
MAP3K7Protein6885 (Entrez Gene)
MAP4K1Protein11184 (Entrez Gene)
MAPK14Protein1432 (Entrez Gene)
MAPK1Protein5594 (Entrez Gene)
MAPK3Protein5596 (Entrez Gene)
MAPK8Protein5599 (Entrez Gene)
MAPK9Protein5601 (Entrez Gene)
MEF2AProtein4205 (Entrez Gene)
MEF2CProtein4208 (Entrez Gene)
METProtein4233 (Entrez Gene)
MMP12Protein