TGF-beta Signaling Pathway (Homo sapiens)

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NU CY TGFBR1 TGFBR1 TGFBR2 TGFBR2 TGFB1 TGFB1 TGFBR3 TGFBR3 TGFB1 BTRC CUL1 RBX1 SKP1 APC PP1 PPP2 of tight Dissolution NF-kB pathway Cofilin Gene expression ERK dependent junctions TGF beta Signaling Pathway SMURF1 STRAP TRAP1 SMAD7 ZFYVE16 P SHC1 PARD6A AXIN1 DAB2 TGIF1 NEDD4L SMURF2 RNF111 P MAPK14 P MAP2K3 P MAP2K6 UCHL5 SPTBN1 ATF2 DCP1A PDK1 P AKT1 P GRB2 SOS1 RHOA CAV1 WWP1 SMURF1 ITCH SMAD7 TRAF6 MYC COL1A2 SP1 CDKN2B MET APP SMAD7 SMAD7 SMURF1 SMURF2 TP53 EID2 SKI NUP214 ETS1 TNC NUP153 ZEB2 TERT SNW1 FOXH1 SKIL ZEB1 CDKN1A PPM1A RUNX2 SNIP1 JUNB STAMBPL1 MYC NUP153 NUP214 KLF11 KLF6 SMAD7 KLF10 FOXP3 KLF10 WWP1 SIK1 UBE2I PIAS1 PIAS2 SUMO1 PJA1 NEDD9 TGFB1I1 COPS5 COPS5 YAP1 RNF111 RAS P RAF1 PAK2 LIMK2 ROCK1 MAPK14 P BCAR1 SRC PRKAR2A P MAP2K4 P MAP4K1 CCND1 CITED1 ATF3 MMP12 MMP1 ITGB4 ITGA2 THBS1 FN1 MTOR S6K RBL2 ITGB3 ITGB1 P PTK2 RAC1 CDC42 CCNB2 CDK1 SKP1 CUL1 BTRC RBX1 PIK3R2 PIK3R1 MAP2K1 MAP2K2 MAPK1 MAPK3 P MAPK8 P MAPK9 P MAPK9 P MAPK8 P MAPK1 P MAPK3 MEF2A MEF2C FOS JUN FOSB JUND P RBL1 E2F5 E2F4 TFDP1 EP300 CREBBP HDAC1 SIN3A HGS PML ZFYVE9 MAP3K7 TAB1 SMAD4 SMAD3 SMAD2 SMAD2 SMAD4 SMAD3 SMAD4 Protein Protein mRNA Ligand Receptor Protein Protein - protein dissociation Enzyme Complex Small molecule Induced activation Inhibition Auto catalysis Transport Positive regulation of gene expression Leads to through unknown mechanism Negative regulation of gene expression Translocation Ubiquitination Deubiquitination Sumoylation Induced catalysis Protein-protein interaction Acetylation Dephosphorylation LEGEND Phosphorylation Deacetylation Golgi apparatus Endosome Nucleus Mitochondrion Desumoylation Methylation Demethylation Palmitoylation Cytoplasm EC Plasma membrane MT Endoplasmic reticulum CY PM GO NU Extracellular ER EN Proteolytic cleavage Molecule P CY NU CY NU CY NU CY NU CY NU CY NU CY NU CY NU CY NU CY NU Name: TGF-beta Signaling Pathway License: Freely available under Creative Commons license Organism: Homo sapiens


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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Ontology Terms

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Bibliography

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History

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RevisionActionTimeUserComment
90028view 12:37, 8 October 2016AlexanderPicoModified description
87408view 04:09, 22 July 2016MkutmonModified description
87394view 04:05, 22 July 2016MaintBotadded missing graphids
86819view 11:55, 11 July 2016KhanspersQuick edit to datanode annotation or property
84196view 16:15, 28 January 2016KhanspersRemoved redundant legend
84195view 16:11, 28 January 2016KhanspersRemoved redundant legend and random extra arc
83869view 17:52, 17 December 2015AlexanderPicoModified title
79966view 08:00, 28 April 2015Zariannotated COL1A2
79341view 06:12, 21 March 2015EgonwRandom change to trigger update to the GPML 2013a schema.
79340view 06:08, 21 March 2015EgonwReverted to version '04:16, 17 April 2013' by Egonw
69026view 10:49, 8 July 2013MaintBotUpdated to 2013 gpml schema
61702view 21:16, 16 April 2013MaintBotfixed missing xrefs
61682view 14:49, 16 April 2013MaintBotfixed xrefs
61678view 14:41, 16 April 2013MaintBot
47976view 07:31, 23 April 2012NetPathModified description
45152view 18:34, 6 October 2011AlexanderPicofixed db ref
45088view 13:58, 6 October 2011KhanspersOntology Term : 'transforming growth factor-beta superfamily mediated signaling pathway' added !
44604view 14:19, 21 September 2011KhanspersUpdating content to NetSlim
44119view 13:49, 24 August 2011KhanspersReverted to version '23:44, 1 March 2011' by Khanspers
44048view 16:45, 22 August 2011KhanspersModified description
44047view 16:43, 22 August 2011KhanspersUpdating pathway from NetSlim
41205view 16:44, 1 March 2011MaintBotRemoved redundant pathway information and comments
35302view 16:29, 11 February 2010NsalomonisModified description
35301view 16:26, 11 February 2010NsalomonisModified description
21445view 04:31, 14 November 2008MaintBot[[Pathway:Homo sapiens:TGF-beta-Receptor NetPath 7]] moved to [[Pathway:WP366]]: Moved to stable identifier
8434view 06:46, 7 January 2008MaintBot[[Pathway:Human:TGF-beta-Receptor NetPath 7]] moved to [[Pathway:Homo sapiens:TGF-beta-Receptor NetPath 7]]: Renaming species
7833view 09:21, 18 December 2007MaintBotfixed category names
7304view 05:42, 4 November 2007MaintBotAdded categories to GPML
6397view 15:18, 22 May 2007A.Pandeygpml file for [[Human:TGF-beta-Receptor_NetPath_7]]

External references

DataNodes

View all...
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)
MMP12Protein4321 (Entrez Gene)
MMP1Protein4312 (Entrez Gene)
MTORProtein207 (Entrez Gene)
MYCProtein4609 (Entrez Gene)
NEDD4LProtein23327 (Entrez Gene)
NEDD9Protein4739 (Entrez Gene)
NUP153Protein9972 (Entrez Gene)
NUP214Protein8021 (Entrez Gene)
PAK2Protein5062 (Entrez Gene)
PARD6AProtein50855 (Entrez Gene)
  • Mediates epithelial-mesenchymal transition
  • GO:0045217
PDK1Protein5163 (Entrez Gene)
PIAS1Protein8554 (Entrez Gene)
PIAS2Protein9063 (Entrez Gene)
PIK3R1Protein5295 (Entrez Gene)
PIK3R2Protein5296 (Entrez Gene)
PJA1Protein64219 (Entrez Gene)
PMLProtein5371 (Entrez Gene)
PPM1AProtein5494 (Entrez Gene)
PRKAR2AProtein5576 (Entrez Gene)
PTK2Protein5747 (Entrez Gene)
RAC1Protein5879 (Entrez Gene)
RAF1Protein5894 (Entrez Gene)
RASProtein387 (Entrez Gene)
RBL1Protein5933 (Entrez Gene)
RBL2Protein5934 (Entrez Gene)
RBX1Protein9978 (Entrez Gene)
RHOAProtein387 (Entrez Gene)
RNF111Protein54778 (Entrez Gene)
ROCK1Protein6093 (Entrez Gene)
RUNX2Protein860 (Entrez Gene)
S6KProtein207 (Entrez Gene)
SHC1Protein6464 (Entrez Gene)
SIK1Protein150094 (Entrez Gene)
SIN3AProtein25942 (Entrez Gene)
SKIProtein6497 (Entrez Gene)
SKILProtein6498 (Entrez Gene)
SKP1Protein6500 (Entrez Gene)
SMAD2Protein4087 (Entrez Gene)
SMAD3Protein4088 (Entrez Gene)
SMAD4Protein4089 (Entrez Gene)
SMAD7Protein4092 (Entrez Gene)
SMURF1Protein57154 (Entrez Gene)
SMURF2Protein64750 (Entrez Gene)
SNIP1Protein79753 (Entrez Gene)
SNW1Protein22938 (Entrez Gene)
SOS1Protein6654 (Entrez Gene)
SP1Protein6667 (Entrez Gene)
SPTBN1Protein6711 (Entrez Gene)
SRCProtein6714 (Entrez Gene)
STAMBPL1Protein57559 (Entrez Gene)
STRAPProtein11171 (Entrez Gene)
SUMO1Protein7341 (Entrez Gene)
TAB1Protein10454 (Entrez Gene)
TERTProtein7015 (Entrez Gene)
TFDP1Protein7027 (Entrez Gene)
TGFB1Protein7040 (Entrez Gene)
TGFB1I1Protein7041 (Entrez Gene)
TGFBR1Protein7046 (Entrez Gene)
TGFBR2Protein7048 (Entrez Gene)
TGFBR3Protein7049 (Entrez Gene)
TGIF1Protein7050 (Entrez Gene)
THBS1Protein7057 (Entrez Gene)
TNCProtein3371 (Entrez Gene)
TP53Protein7157 (Entrez Gene)
TRAF6Protein7189 (Entrez Gene)
TRAP1Protein10131 (Entrez Gene)
UBE2IProtein7329 (Entrez Gene)
UCHL5GeneProduct51377 (Entrez Gene)
WWP1Protein11059 (Entrez Gene)
YAP1Protein10413 (Entrez Gene)
ZEB1Protein6935 (Entrez Gene)
ZEB2Protein9839 (Entrez Gene)
ZFYVE16Protein9765 (Entrez Gene)
ZFYVE9Protein9372 (Entrez Gene)

Annotated Interactions

<cite>No annotated interactions</cite>