Identifiers
transforming growth factor beta 1
HUGO:TGFB1 hgnc_id:HGNC:11766 HGNC:11766 ENTREZ:7040 UNIPROT:P01137
transforming growth factor beta 2
HUGO:TGFB2 hgnc_id:HGNC:11768 HGNC:11768 ENTREZ:7042 UNIPROT:P61812
transforming growth factor beta 3
HUGO:TGFB3 hgnc_id:HGNC:11769 HGNC:11769 ENTREZ:7043 UNIPROT:P10600
HUGO:TGFB1 HUGO:TGFB2 HUGO:TGFB3

Maps_Modules
HMC:TUMOR_PROMOTING_INFLAMMATION
HMC:ACTIVATING_INVASION_AND_METASTASIS
 Cancer Associated Fibroblasts   / GROWTH_FACTORS_SIGNALING_PATHWAYS 
 Cancer Associated Fibroblasts   / GROWTH_FACTORS_PRODUCTION 
 Cancer Associated Fibroblasts   / TREG_MODULATORS 
 Innate Immunity   / IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS 
 Innate Immunity   / TUMOR_GROWTH 

References
CASCADE:TNF
PMID:21098712
Cancer TGFB exosomes trigger fibroblast to myofibroblast differentiation
PMID:15653932
Treatment of fibroblasts with TNF-?? resulted in a significant increase in TGF-??1 protein as measured by ELISA. The increase in protein was preceded by a 200???400% increase in TGF-??1 mRNA detected by quantitative, real-time, reverse transcriptase???polymerase chain reaction. Western blot analysis showed that TNF-?? activated the extracellular signal???regulated kinase (ERK), and inhibitors of the ERK-specific mitogen-activated protein kinase pathway (PD98059 or U0126) blocked TNF-?? induction of TGF-??1
PMID:23784029, PMID:16572188, PMID:8515656
TGF-??1 treatment successfully transformed primary resting fibroblasts into CAFs
PMID:19038247
TGFbeta induces fibroblast collagen biosynthesis downstream of CCL7 and via SMAD3.
Thus, ERK, a MAPK family member, phosphorylates serine residues in the linker regions of Smad1???3 and ERK inhibition reduces TGF??-stimulated Smad phosphorylation as well as collagen biosynthesis, suggesting that ERK activation is necessary for an optimal response to TGF?? [9]. Similarly, p38 MAPK has been shown to be central to TGF?? mediated-collagen and fibronectin expression in SSc fibroblasts [10].
PMID:19747910
Through paracrine signaling molecules, TGF-beta and IL-1beta, cancer cells activate stromal fibroblasts and induce the expression of fibroblast activation protein (FAP). FAP, in turn, affects the proliferation, invasion and migration of the cancer cells. We report that TGF-beta and IL-1beta are important factors in inducing differentiation of myofibroblasts and expression of functional markers, notably alpha-SMA.
PMID:18423981
Differential impact of TGF-beta and EGF on fibroblast differentiation and invasion reciprocally promotes colon cancer cell invasion.
PMID:23034983
Inhibition of TGF-beta/Smad signaling by BAMBI blocks differentiation of human mesenchymal stem cells to carcinoma-associated fibroblasts and abolishes their protumor effects
PMID:21041659
Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts
PMID:17768418
TGFbeta is responsible for skin tumour infiltration by macrophages enabling the tumours to escape immune destruction.
TGFbeta-mediated tumour progression was accompanied by an increase in tumour-associated macrophages (TAM) and a decrease in tumour-infiltrating dendritic cells (DCs).
???
both TGF-??1 and TGF-??2 are up-regulated in CAFs
PMID:15265520 , PMID:11279127
TGF/SMAD pathway regulates genes involved in extracellular matrix remodeling
PMID:15003992
TGF-??-mediated myofibroblast differentiation and proliferation of the NRK fibroblasts are mutually exclusive responses to TGF-??. Differentiation into myofibroblasts appears to be the default pathway whereas proliferation becomes the dominant and sole response when both TGF-?? and EGF are present.
TGF-?? induced a strong activation of RhoA and stress fiber formation in fibroblasts,
PMID:17979848
TGF-?? promotes the generation and function of Treg cells
TGF-?? is able to convert CD4+CD25??? non-Treg cells into CD4+CD25+ Treg cells, and this conversion was accompanied with increased Foxp3 expression
PMID:26201938
The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs.
PMID:22874531
TGFB treatment induces the autophagy-mediated downregulation of Cav-1 in fibroblasts.
 MACROPHAGE 
 MDSC 
 NATURAL_KILLER 
 DENDRITIC_CELL 
 MAST_CELL 
 NEUTROPHIL 
CASCADE:TGFB
CASCADE:STING
CASCADE:STAB2
CASCADE:TLR2_4
CASCADE:IFNG
PMID:24132110
TGFB has been identified as a factor that inhibits the functional maturation of this cell population9. Immature NK cells do not respond to foreign antigens, thus exposure of NK cells to TGF?? will impair the recognition and the clearance of tumour cells. The inhibition of maturation also prevents the systemic effects of NK cells,
for example, activation of antigen-presenting dendritic cells and inhibition of interferon-?? (IFN??) secretion, which drives T helper 1 cell (TH1 cell) maturation
TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGF?? receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation.
PMID:17070508, PMID:18490733
TGFB downregulates NKG2D expression.
IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-?? in NK cells via the c-Jun N-terminal kinase (JNK) pathway
PMID:2871107
Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness.
PMID:20538542
TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression.
The roles of TGF?? in the tumour microenvironment.
PMID:20616810
The polarization of immune cells in the tumour environment by TGFbeta.
PMID:22703233
TGFB1 participates in M2 activation.
PMID:7594497
TGFB1 upregulates IL10 expression in macrophages.
TGFB1 and IL10 dowregulate expression of TNF.
PMID:21278795
TGFB-induced IRAK3 (IRAK-M) expression in tumor-associated macrophages
and inhibit TLR-dependent signaling
PMID:20644162
Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGF??, VEGF.
PMID:19109155
MDSC inhibit cytotoxicity, NKG2D expression, and IFN-gamma production of NK cells both in vitro and in vivo.
Membrane-bound TGF-beta1 on MDSC is responsible for MDSC-mediated suppression of NK cells.
PMID:21372296
HMGB1 induces the production of angiogenic factors VEGF, and TGFB1 by macrophage via TLR4-dependent mechanisms.
PMID:16424049
IFNG induces INOS and IL10 expression and TGFB secretion in MDSC
PMID:15099563
Mast cells produce cytokines TNF-a, TGF-b, IFN-a, IL-1a, IL-1b, IL-5, IL-6,
IL-13, IL-16, IL-18
PMID:26966341
tudies have shown that, analogously to the M1 and M2 dichotomy, TANs develop a protumorigenic (N2) phenotype in untreated tumors, largely driven by the presence of TGF-??

References
ca_re284( Cancer Associated Fibroblasts  ):
PMID:11875494
IL10-induced p38 phosphorylation.
PMID:20435894
SHIP inhibit MAPKp38 activation and prevent
MKNK1 phosphorylation by inhibiting the p38MAPK
pathway downstream of IL10.
PMID:10925299
IL13 induces p38 MAPK phosphorilation and activation, p38 MAPK participates in arginase activation??downstream of IL13.
PMID:23508573
HMGB1 induces activation (phosphorylation) of p38 via TLR4.
PMID:12811837, PMID:16713974
TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling.
PMID:16713974
TLR2 activates (induces phosphorylation of) ERKs, JNKs, and p38 rapidly and transiently in control macrophages.
This activation is inhibited by IFNG signaling.
PMID:11438547, PMID:24378531
Both TNFR1 and TNFR2 signaling pathways are needed for activation of p38 MAPK.
ca_re410( Cancer Associated Fibroblasts  ):
CASCADE:LIF
PMID:22595692
The structure of receptors of IL6 like cytokines

1. TGFB*@Cytosol

1. TGFB*@INNATE_IMMUNE_CELL_Cytosol

1. TGFB*@INNATE_IMMUNE_CELL_Membrane

1. TGFB*@default

1. LAP:​LTBP*:​TGFB*@Cytosol
2. TGFB*:​TGFBR1:​TGFBR2@Cytosol

1. TGFB*:​TGFBR1:​TGFBR2@INNATE_IMMUNE_CELL_Membrane

1. LAP:​LTBP*:​TGFB*@Treg modulation

1. LAP:​LTBP*:​TGFB*@default

1. rTGFB*@Cytosol → TGFB*@Cytosol
2. TGFBR1@Cytosol + TGFBR2@Cytosol + TGFB*@default → TGFB*:​TGFBR1:​TGFBR2@Cytosol
3. TGFB*@default → MIGRATION_INTO_THE_TUMOR@default
4. LAP:​LTBP*:​TGFB*@Cytosol → GROWTH_FACTORS_PRODUCTION@default
5. LAP:​LTBP*:​TGFB*@default → TGFB*@default + LAP@default + LTBP*@default
6. TGFB*@Cytosol + LTBP*@Cytosol + LAP@Cytosol → LAP:​LTBP*:​TGFB*@Cytosol
7. LAP:​LTBP*:​TGFB*@Cytosol → LAP:​LTBP*:​TGFB*@default
8. TGFB*@default + EGF@default → Fibroblast_proliferation@Cytosol
9. LAP:​LTBP*:​TGFB*@Cytosol → LAP:​LTBP*:​TGFB*@Treg modulation
10. TGFB*@default → ECM_REGULATION@default
11. TGFB*@INNATE_IMMUNE_CELL_Cytosol → TGFB*@default
12. TGFB*@INNATE_IMMUNE_CELL_Cytosol → TGFB*@INNATE_IMMUNE_CELL_Membrane
13. TGFB*@INNATE_IMMUNE_CELL_Membrane → TUMOR_GROWTH@TUMOR_CELL_AS_EFFECTOR
14. TGFB1@INNATE_IMMUNE_CELL_Cytosol → TGFB*@INNATE_IMMUNE_CELL_Cytosol
15. TGFB2@INNATE_IMMUNE_CELL_Cytosol → TGFB*@INNATE_IMMUNE_CELL_Cytosol
16. TGFB3@INNATE_IMMUNE_CELL_Cytosol → TGFB*@INNATE_IMMUNE_CELL_Cytosol
17. TGFB*@INNATE_IMMUNE_CELL_Cytosol → IMMUNE_SUPRESSION@default
18. TGFBR1@INNATE_IMMUNE_CELL_Membrane + TGFBR2@INNATE_IMMUNE_CELL_Membrane + TGFB*@default → TGFB*:​TGFBR1:​TGFBR2@INNATE_IMMUNE_CELL_Membrane

1. gIL6@Cytosol → rIL6@Cytosol
2. gCCL5@Cytosol → rCCL5@Cytosol
3. gTGFB*@Cytosol → rTGFB*@Cytosol
4. SMAD3@Cytosol → SMAD3|​pho@Cytosol
5. SMAD2@Cytosol → SMAD2|​pho@Cytosol
6. rSMAD3@Cytosol → SMAD3@Cytosol
7. p38*@Cytosol → p38*|​pho|​active@Cytosol
8. rSMAD4@Cytosol → SMAD4@Cytosol
9. gMIR21@Cytosol → arMIR21@Cytosol
10. gCXCL12@Cytosol → rCXCL12@Cytosol
11. gBMP4@Cytosol → rBMP4@Cytosol
12. gCXCL7@Cytosol → rCXCL7@Cytosol
13. gCXCL5@Cytosol → rCXCL5@Cytosol
14. FN*@Cytosol → ECM_REGULATION@default
15. gIL6R@Cytosol → rIL6R@Cytosol
16. ggp130*@Cytosol → rgp130@Cytosol
17. EGR1@Cytosol → EGR1@Cytosol
18. ERK1/2*@Cytosol → ERK1/2*|​pho@Cytosol
19. rILK@Cytosol → ILK@Cytosol
20. ca_s810 + GTP@Cytosol → ca_s813 + GDP@Cytosol
21. gLIF@Cytosol → rLIF@Cytosol
22. gIL11@Cytosol → rIL11@Cytosol
23. gPDGFR*@Cytosol → rPDGFR*@Cytosol
24. gP4HTM@Cytosol → rP4HTM@Cytosol
25. gIGF1@Cytosol → rIGF1@Cytosol
26. gSERPINE1@Cytosol → rSERPINE1@Cytosol
27. CAV1@Cytosol → degraded
28. rCAV1@Cytosol → CAV1@Cytosol
29. gPDGF*@Cytosol → rPDGF*@Cytosol
30. IQGAP1 @Cytosol + TGFBR2@Cytosol → IQGAP1 :​TGFBR2@Cytosol
31. gEGF@Cytosol → rEGF@Cytosol
32. Collagens*@Cytosol → ECM_REGULATION@default
33. gGPT2@Cytosol → rGPT2@Cytosol
34. gMIR424@Cytosol → arMIR424@Cytosol
35. rACTA2@Cytosol → ACTA2@Cytosol
36. THBS1@INNATE_IMMUNE_CELL_Cytosol → THBS1@default
37. gTNF@INNATE_IMMUNE_CELL_Cytosol → rTNF@INNATE_IMMUNE_CELL_Cytosol
38. gMIR183@INNATE_IMMUNE_CELL_Cytosol → arMIR183@INNATE_IMMUNE_CELL_Cytosol
39. gCCL5@INNATE_IMMUNE_CELL_Cytosol → rCCL5@INNATE_IMMUNE_CELL_Cytosol
40. gNKG2D*@INNATE_IMMUNE_CELL_Cytosol → rNKG2D*@INNATE_IMMUNE_CELL_Cytosol
41. gNKp30*@INNATE_IMMUNE_CELL_Cytosol → rNKp30*@INNATE_IMMUNE_CELL_Cytosol
42. SMAD3@INNATE_IMMUNE_CELL_Cytosol → SMAD3|​pho@INNATE_IMMUNE_CELL_Cytosol
43. gMIR1245A@INNATE_IMMUNE_CELL_Cytosol → arMIR1245A@INNATE_IMMUNE_CELL_Cytosol
44. gMIR185@INNATE_IMMUNE_CELL_Cytosol → arMIR185@INNATE_IMMUNE_CELL_Cytosol
45. SMAD2@INNATE_IMMUNE_CELL_Cytosol → SMAD2|​pho@INNATE_IMMUNE_CELL_Cytosol
46. gIL10@INNATE_IMMUNE_CELL_Cytosol → rIL10@INNATE_IMMUNE_CELL_Cytosol
47. O_sub_2_endsub_@INNATE_IMMUNE_CELL_Cytosol → O_sub_2_endsub__super_-_endsuper_@INNATE_IMMUNE_CELL_Cytosol
48. gCCL3@INNATE_IMMUNE_CELL_Cytosol → rCCL3@INNATE_IMMUNE_CELL_Cytosol
49. gCCL2@INNATE_IMMUNE_CELL_Cytosol → rCCL2@INNATE_IMMUNE_CELL_Cytosol
50. gIRAK3@INNATE_IMMUNE_CELL_Cytosol → rIRAK3@INNATE_IMMUNE_CELL_Cytosol