Transforming growth factor beta-1 proprotein (P01137)

Uniprot ID	P01137
Protein Name	Transforming growth factor beta-1 proprotein
Gene Name	TGFB1
Species	Homo sapiens (Human)

Signal peptide^(a)	Y	Secretome P^(b)	0.886
Function	Transforming growth factor beta-1 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains, which constitute the regulatory and active subunit of TGF-beta-1, respectively. .[Latency-associated peptide]: Required to maintain the Transforming growth factor beta-1 (TGF-beta-1) chain in a latent state during storage in extracellular matrix (PubMed:28117447). Associates non-covalently with TGF-beta-1 and regulates its activation via interaction with 'milieu molecules', such as LTBP1, LRRC32/GARP and LRRC33/NRROS, that control activation of TGF-beta-1 (PubMed:2022183, PubMed:8617200, PubMed:8939931, PubMed:19750484, PubMed:22278742, PubMed:19651619). Interaction with LRRC33/NRROS regulates activation of TGF-beta-1 in macrophages and microglia (Probable). Interaction with LRRC32/GARP controls activation of TGF-beta-1 on the surface of activated regulatory T-cells (Tregs) (PubMed:19750484, PubMed:22278742, PubMed:19651619). Interaction with integrins (ITGAV:ITGB6 or ITGAV:ITGB8) results in distortion of the Latency-associated peptide chain and subsequent release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447). {ECO:0000269\|PubMed:19651619, ECO:0000269\|PubMed:19750484, ECO:0000269\|PubMed:2022183, ECO:0000269\|PubMed:22278742, ECO:0000269\|PubMed:28117447, ECO:0000269\|PubMed:8617200, ECO:0000269\|PubMed:8939931, ECO:0000305\|PubMed:29909984}.Transforming growth factor beta-1: Multifunctional protein that regulates the growth and differentiation of various cell types and is involved in various processes, such as normal development, immune function, microglia function and responses to neurodegeneration (By similarity). Activation into mature form follows different steps: following cleavage of the proprotein in the Golgi apparatus, Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains remain non-covalently linked rendering TGF-beta-1 inactive during storage in extracellular matrix (PubMed:29109152). At the same time, LAP chain interacts with 'milieu molecules', such as LTBP1, LRRC32/GARP and LRRC33/NRROS that control activation of TGF-beta-1 and maintain it in a latent state during storage in extracellular milieus (PubMed:2022183, PubMed:8617200, PubMed:8939931, PubMed:19750484, PubMed:22278742, PubMed:19651619). TGF-beta-1 is released from LAP by integrins (ITGAV:ITGB6 or ITGAV:ITGB8): integrin-binding to LAP stabilizes an alternative conformation of the LAP bowtie tail and results in distortion of the LAP chain and subsequent release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447). Once activated following release of LAP, TGF-beta-1 acts by binding to TGF-beta receptors (TGFBR1 and TGFBR2), which transduce signal (PubMed:20207738). While expressed by many cells types, TGF-beta-1 only has a very localized range of action within cell environment thanks to fine regulation of its activation by Latency-associated peptide chain (LAP) and 'milieu molecules' (By similarity). Plays an important role in bone remodeling: acts as a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts (By similarity). Can promote either T-helper 17 cells (Th17) or regulatory T-cells (Treg) lineage differentiation in a concentration-dependent manner (By similarity). At high concentrations, leads to FOXP3-mediated suppression of RORC and down-regulation of IL-17 expression, favoring Treg cell development (By similarity). At low concentrations in concert with IL-6 and IL-21, leads to expression of the IL-17 and IL-23 receptors, favoring differentiation to Th17 cells (By similarity). Stimulates sustained production of collagen through the activation of CREB3L1 by regulated intramembrane proteolysis (RIP) (PubMed:25310401). Mediates SMAD2/3 activation by inducing its phosphorylation and subsequent translocation to the nucleus (PubMed:25893292, PubMed:29483653, PubMed:30696809). Can induce epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types (PubMed:25893292, PubMed:30696809). {ECO:0000250\|UniProtKB:P04202, ECO:0000269\|PubMed:19651619, ECO:0000269\|PubMed:19750484, ECO:0000269\|PubMed:20207738, ECO:0000269\|PubMed:2022183, ECO:0000269\|PubMed:22278742, ECO:0000269\|PubMed:25310401, ECO:0000269\|PubMed:25893292, ECO:0000269\|PubMed:28117447, ECO:0000269\|PubMed:29109152, ECO:0000269\|PubMed:29483653, ECO:0000269\|PubMed:30696809, ECO:0000269\|PubMed:8617200, ECO:0000269\|PubMed:8939931}.
GO - Molecular function	antigen binding : IPI:UniProtKB cytokine activity : IBA:GO_Central enzyme binding : IPI:BHF-UCL growth factor activity : IEA:UniProtKB-KW identical protein binding : IPI:IntAct transforming growth factor beta receptor binding : IBA:GO_Central type I transforming growth factor beta receptor binding : IMP:AgBase type II transforming growth factor beta receptor binding : IDA:BHF-UCL type III transforming growth factor beta receptor binding : IMP:AgBase
GO - Biological process	aortic valve morphogenesis : IMP:BHF-UCL ATP biosynthetic process : IDA:BHF-UCL BMP signaling pathway : IBA:GO_Central cell cycle arrest : IDA:BHF-UCL cell development : IBA:GO_Central cell migration : IDA:UniProtKB cell-cell junction organization : IDA:BHF-UCL cellular response to organic cyclic compound : IDA:UniProtKB cellular response to transforming growth factor beta stimulus : IDA:BHF-UCL chondrocyte differentiation : IDA:UniProtKB common-partner SMAD protein phosphorylation : IDA:UniProtKB connective tissue replacement involved in inflammatory response wound healing : TAS:BHF-UCL cytokine-mediated signaling pathway : TAS:Reactome embryonic liver development : ISS:BHF-UCL epidermal growth factor receptor signaling pathway : IDA:BHF-UCL epithelial to mesenchymal transition : IDA:UniProtKB extracellular matrix assembly : IDA:BHF-UCL extrinsic apoptotic signaling pathway : IDA:BHF-UCL heart development : ISS:BHF-UCL heart valve morphogenesis : ISS:BHF-UCL hematopoietic progenitor cell differentiation : IDA:UniProtKB hyaluronan catabolic process : IDA:UniProtKB inflammatory response : IDA:UniProtKB leukocyte migration : TAS:Reactome lipopolysaccharide-mediated signaling pathway : IDA:UniProtKB lymph node development : ISS:UniProtKB macrophage derived foam cell differentiation : IC:BHF-UCL MAPK cascade : IMP:UniProtKB membrane protein intracellular domain proteolysis : IDA:UniProtKB mitotic cell cycle checkpoint : IDA:BHF-UCL negative regulation of biomineral tissue development : IDA:BHF-UCL negative regulation of blood vessel endothelial cell migration : IDA:BHF-UCL negative regulation of cell cycle : IDA:HGNC-UCL negative regulation of cell differentiation : IEP:CACAO negative regulation of cell growth : IDA:BHF-UCL negative regulation of cell population proliferation : IDA:BHF-UCL negative regulation of cell-cell adhesion : IDA:BHF-UCL negative regulation of cytolysis : IDA:ARUK-UCL negative regulation of epithelial cell proliferation : IDA:BHF-UCL negative regulation of extracellular matrix disassembly : IC:BHF-UCL negative regulation of fat cell differentiation : IDA:UniProtKB negative regulation of gene expression : IDA:BHF-UCL negative regulation of gene silencing by miRNA : IGI:BHF-UCL negative regulation of hyaluronan biosynthetic process : IDA:UniProtKB negative regulation of macrophage cytokine production : IDA:DFLAT negative regulation of mitotic cell cycle : IDA:BHF-UCL negative regulation of myoblast differentiation : IDA:UniProtKB negative regulation of production of miRNAs involved in gene silencing by miRNA : IGI:BHF-UCL negative regulation of protein localization to plasma membrane : IDA:UniProtKB negative regulation of protein phosphorylation : IDA:BHF-UCL negative regulation of skeletal muscle tissue development : IDA:UniProtKB negative regulation of transcription, DNA-templated : IDA:UniProtKB negative regulation of transforming growth factor beta receptor signaling pathway : TAS:Reactome neural tube closure : ISS:BHF-UCL neural tube development : ISS:BHF-UCL ossification involved in bone remodeling : IEP:BHF-UCL pathway-restricted SMAD protein phosphorylation : IDA:UniProtKB phosphate-containing compound metabolic process : IDA:BHF-UCL platelet degranulation : TAS:Reactome positive regulation of blood vessel endothelial cell migration : IDA:BHF-UCL positive regulation of bone mineralization : IEP:BHF-UCL positive regulation of cardiac muscle cell differentiation : IDA:BHF-UCL positive regulation of cell division : IEA:UniProtKB-KW positive regulation of cell migration : IDA:BHF-UCL positive regulation of cell population proliferation : IDA:BHF-UCL positive regulation of cellular protein metabolic process : IDA:BHF-UCL positive regulation of chemotaxis : IDA:BHF-UCL positive regulation of collagen biosynthetic process : IDA:UniProtKB positive regulation of epithelial to mesenchymal transition : IDA:BHF-UCL positive regulation of ERK1 and ERK2 cascade : IDA:UniProtKB positive regulation of extracellular matrix assembly : IC:BHF-UCL positive regulation of fibroblast migration : IDA:BHF-UCL positive regulation of gene expression : IDA:UniProtKB positive regulation of interleukin-17 production : IDA:BHF-UCL positive regulation of isotype switching to IgA isotypes : IDA:MGI positive regulation of MAP kinase activity : IDA:BHF-UCL positive regulation of microglia differentiation : ISS:UniProtKB positive regulation of NAD+ ADP-ribosyltransferase activity : IDA:BHF-UCL positive regulation of pathway-restricted SMAD protein phosphorylation : IDA:BHF-UCL positive regulation of peptidyl-serine phosphorylation : IDA:BHF-UCL positive regulation of peptidyl-threonine phosphorylation : IDA:BHF-UCL positive regulation of peptidyl-tyrosine phosphorylation : IDA:UniProtKB positive regulation of phosphatidylinositol 3-kinase activity : IDA:BHF-UCL positive regulation of pri-miRNA transcription by RNA polymerase II : IDA:BHF-UCL positive regulation of production of miRNAs involved in gene silencing by miRNA : IDA:BHF-UCL positive regulation of protein complex assembly : IDA:BHF-UCL positive regulation of protein dephosphorylation : IDA:BHF-UCL positive regulation of protein import into nucleus : IDA:BHF-UCL positive regulation of protein kinase B signaling : IDA:BHF-UCL positive regulation of protein localization to nucleus : IDA:BHF-UCL positive regulation of protein phosphorylation : IDA:BHF-UCL positive regulation of protein secretion : IDA:BHF-UCL positive regulation of SMAD protein signal transduction : IDA:BHF-UCL positive regulation of superoxide anion generation : IDA:BHF-UCL positive regulation of transcription by RNA polymerase II : IDA:UniProtKB positive regulation of transcription regulatory region DNA binding : IDA:BHF-UCL positive regulation of transcription, DNA-templated : IDA:UniProtKB positive regulation of vascular endothelial growth factor production : TAS:BHF-UCL positive regulation of vascular permeability : IDA:UniProtKB protein export from nucleus : IDA:UniProtKB protein kinase B signaling : IMP:UniProtKB protein phosphorylation : ISS:UniProtKB receptor catabolic process : IDA:BHF-UCL regulation of apoptotic process : IBA:GO_Central regulation of binding : ISS:UniProtKB regulation of blood vessel remodeling : NAS:BHF-UCL regulation of cell migration : TAS:BHF-UCL regulation of cell population proliferation : IBA:GO_Central regulation of DNA binding : ISS:UniProtKB regulation of MAPK cascade : IBA:GO_Central regulation of protein import into nucleus : ISS:UniProtKB regulation of SMAD protein signal transduction : IDA:UniProtKB regulation of striated muscle tissue development : ISS:UniProtKB regulation of transforming growth factor beta receptor signaling pathway : IDA:BHF-UCL response to cholesterol : IDA:BHF-UCL response to estradiol : IDA:BHF-UCL response to progesterone : IDA:BHF-UCL response to wounding : IEP:BHF-UCL salivary gland morphogenesis : IEP:BHF-UCL SMAD protein complex assembly : IDA:BHF-UCL SMAD protein signal transduction : IBA:GO_Central transforming growth factor beta receptor signaling pathway : IDA:BHF-UCL transforming growth factor beta receptor signaling pathway involved in heart development : ISS:BHF-UCL vasculogenesis : ISS:BHF-UCL ventricular cardiac muscle tissue morphogenesis : ISS:BHF-UCL

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^{(a) The Signal peptide D-score cutoff for "YES"(having signal peptide) is 0.45.}
^{(b) Non-classically secreted proteins should obtain an NN-score(Neural Networks score) exceeding the normal threshold of 0.5, but not at the same time be predicted to contain a signal peptide.}