TGF-beta signaling pathway (WP366)

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, please cite the 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
last edited

Authors

A.Pandey, MaintBot, Nsalomonis, Khanspers, AlexanderPico, NetPath, Egonw, Zari, Mkutmon, L Dupuis, DeSl, and Eweitz

Cited In

Organism

Homo sapiens

Communities

CPTAC

Annotations

Pathway Ontology: transforming growth factor-beta superfamily mediated signaling pathway

Participants

Label Type Compact Identifier
SKI Protein ncbigene:6497
MAPK1 Protein ncbigene:5594
DAB2 Protein ncbigene:1601
SMAD7 Protein ncbigene:4092
SMAD3 Protein ncbigene:4088
MAPK8 Protein ncbigene:5599
SIK1 Protein ncbigene:150094
RNF111 Protein ncbigene:54778
SP1 Protein ncbigene:6667
ATF2 Protein ncbigene:1386
E2F5 Protein ncbigene:1875
FOXP3 Protein ncbigene:50943
JUNB Protein ncbigene:3726
CDK1 Protein ncbigene:983
SMAD7 Protein ncbigene:4092
DCP1A Protein ncbigene:55802
WWP1 Protein ncbigene:11059
KLF10 Protein ncbigene:7071
NEDD9 Protein ncbigene:4739
TGFB1 Protein ncbigene:7040
SMAD7 Protein ncbigene:4092
NUP214 Protein ncbigene:8021
CDKN1A Protein ncbigene:1026
SMURF1 Protein ncbigene:57154
CREBBP Protein ncbigene:1387
SMURF1 Protein ncbigene:57154
NUP214 Protein ncbigene:8021
COPS5 Protein ncbigene:10987
EP300 Protein ncbigene:2033
PML Protein ncbigene:5371
SPTBN1 Protein ncbigene:6711
PJA1 Protein ncbigene:64219
TGFBR1 Protein ncbigene:7046
MAP3K7 Protein ncbigene:6885
LIMK2 Protein ncbigene:3985
PRKAR2A Protein ncbigene:5576
SMAD4 Protein ncbigene:4089
WWP1 Protein ncbigene:11059
STRAP Protein ncbigene:11171
CCND1 Protein ncbigene:595
CDKN2B Protein ncbigene:1030
UBE2I Protein ncbigene:7329
MAPK9 Protein ncbigene:5601
ITCH Protein ncbigene:83737
ZEB2 Protein ncbigene:9839
S6K Protein ncbigene:207
MEF2A Protein ncbigene:4205
ZFYVE9 Protein ncbigene:9372
MAPK14 Protein ncbigene:1432
RBL2 Protein ncbigene:5934
MTOR Protein ncbigene:207
MYC Protein ncbigene:4609
RAS Protein ncbigene:387
THBS1 Protein ncbigene:7057
RHOA Protein ncbigene:387
RNF111 Protein ncbigene:54778
MAPK3 Protein ncbigene:5596
AXIN1 Protein ncbigene:8312
SOS1 Protein ncbigene:6654
UCHL5 GeneProduct ncbigene:51377
CDC42 Protein ncbigene:998
TGFBR2 Protein ncbigene:7048
KLF6 Protein ncbigene:1316
ATF3 Protein ncbigene:467
NEDD4L Protein ncbigene:23327
MMP12 Protein ncbigene:4321
SMAD2 Protein ncbigene:4087
MAPK14 Protein ncbigene:1432
STAMBPL1 Protein ncbigene:57559
NUP153 Protein ncbigene:9972
MET Protein ncbigene:4233
BTRC Protein ncbigene:8945
TGIF1 Protein ncbigene:7050
MAP2K1 Protein ncbigene:5604
RAF1 Protein ncbigene:5894
SMURF2 Protein ncbigene:64750
SNW1 Protein ncbigene:22938
E2F4 Protein ncbigene:1874
SKP1 Protein ncbigene:6500
ETS1 Protein ncbigene:2113
EID2 Protein ncbigene:163126
RBX1 Protein ncbigene:9978
TP53 Protein ncbigene:7157
CAV1 Protein ncbigene:857
SMAD2 Protein ncbigene:4087
TGFB1I1 Protein ncbigene:7041
SHC1 Protein ncbigene:6464
MYC Protein ncbigene:4609
MAPK8 Protein ncbigene:5599
MAP2K2 Protein ncbigene:5605
SMURF1 Protein ncbigene:57154
SMAD7 Protein ncbigene:4092
BTRC Protein ncbigene:8945
FOXH1 Protein ncbigene:8928
ITGB1 Protein ncbigene:3688
MAPK1 Protein ncbigene:5594
SKIL Protein ncbigene:6498
COPS5 Protein ncbigene:10987
FN1 Protein ncbigene:2335
MAP4K1 Protein ncbigene:11184
SMAD3 Protein ncbigene:4088
CITED1 Protein ncbigene:4435
TGFBR1 Protein ncbigene:7046
ITGB3 Protein ncbigene:3690
PIK3R2 Protein ncbigene:5296
RAC1 Protein ncbigene:5879
TFDP1 Protein ncbigene:7027
TGFBR2 Protein ncbigene:7048
PIK3R1 Protein ncbigene:5295
CUL1 Protein ncbigene:8454
PAK2 Protein ncbigene:5062
KLF10 Protein ncbigene:7071
APP Protein ncbigene:351
CCNB2 Protein ncbigene:9133
MAP2K6 Protein ncbigene:5608
PPM1A Protein ncbigene:5494
HDAC1 Protein ncbigene:3065
KLF11 Protein ncbigene:8462
TERT Protein ncbigene:7015
PIAS1 Protein ncbigene:8554
JUN Protein ncbigene:3725
SUMO1 Protein ncbigene:7341
MMP1 Protein ncbigene:4312
TRAP1 Protein ncbigene:10131
TGFB1 Protein ncbigene:7040
ROCK1 Protein ncbigene:6093
BCAR1 Protein ncbigene:9564
AKT1 Protein ncbigene:207
SIN3A Protein ncbigene:25942
TNC Protein ncbigene:3371
FOS Protein ncbigene:2353
MEF2C Protein ncbigene:4208
MAP2K4 Protein ncbigene:6416
MAP2K3 Protein ncbigene:5606
SKP1 Protein ncbigene:6500
SRC Protein ncbigene:6714
COL1A2 Protein ncbigene:1278
TGFB1 Protein ncbigene:7040
ZFYVE16 Protein ncbigene:9765
RBX1 Protein ncbigene:9978
SMAD4 Protein ncbigene:4089
ITGA2 Protein ncbigene:3673
JUND Protein ncbigene:3727
GRB2 Protein ncbigene:2885
ZEB1 Protein ncbigene:6935
TRAF6 Protein ncbigene:7189
PIAS2 Protein ncbigene:9063
NUP153 Protein ncbigene:9972
SMAD7 Protein ncbigene:4092
PDK1 Protein ncbigene:5163
TGFBR3 Protein ncbigene:7049
RBL1 Protein ncbigene:5933
PTK2 Protein ncbigene:5747
RUNX2 Protein ncbigene:860
SMURF2 Protein ncbigene:64750
FOSB Protein ncbigene:2354
TAB1 Protein ncbigene:10454
SMAD4 Protein ncbigene:4089
YAP1 Protein ncbigene:10413
TGFBR3 Protein ncbigene:7049
HGS Protein ncbigene:9146
ITGB4 Protein ncbigene:3691
CUL1 Protein ncbigene:8454
PARD6A Protein ncbigene:50855
MAPK3 Protein ncbigene:5596
MAPK9 Protein ncbigene:5601
SNIP1 Protein ncbigene:79753

References

  1. Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GSS, Venugopal AK, et al. NetPath: a public resource of curated signal transduction pathways. Genome Biol. 2010 Jan 12;11(1):R3. PubMed Europe PMC Scholia