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![TGFβ Activation continued.....
LATENT TGFβ COMPLEX
• TGF-β1, TGF-β2 and TGF-β3 are synthesized as Precursor
molecule which contains propeptide region in addition
to TGF-β homodimer.
• After synthesized TGF-β homodimer interact with
Latency Associated Peptide (LAP). [LAP is a protein
derived from N-terminal region of TGF-β gene product].
• Interaction of TGF-β homodimer with LAP forms Small
Latent Complex (SLC)
• This complex remains in cell unit is bounded by another
protein called Latent TGF-β Binding Protein (LTBP)
forming large complex called Large Latent Complex (LLC)
• It is LLC that get secreted to Extracellular Matrix (ECM)](https://image.slidesharecdn.com/tgfactivationandsignaling-140316064032-phpapp01/85/Tgf-activation-and-signaling-6-320.jpg)
Uploaded byFathimath Shibana
Tgfβ activation and signaling
TGFβ is a diverse family of growth factors that controls proliferation and cellular differentiation. TGFβ exists in 3 subtypes - TGFβ1, TGFβ2, and TGFβ3. TGFβ is synthesized as a precursor molecule bound to latency associated peptide (LAP) forming the small latent complex, which then binds to latent TGFβ binding protein forming the large latent complex. The large latent complex is activated via proteases or integrins that cleave LAP, releasing active TGFβ to bind receptors and signal downstream. Upon receptor binding, TGFβ phosphorylates SMAD proteins that regulate transcription of target genes controlling various cellular processes.
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Tgfβ activation and signaling
- 1. TGFβ ACTIVATION ANDSIGNALING Presented by: Fathimath Shibana M. Sc Biotechnology 3rd Semester, 2013 University of Mysore Guided by: Dr. Geetha N.P . Assistant Professor DOS in Biotechnology
- 2. WHAT IS TGF? •It is transforming growth factor or tumor growth factor. • There are two types, TGF-α and TGF-β • TGF-α is a single growth factor which is upregulated in some human cancers. It is produced in macrophages, brain cells and keratinocytes (basal cells in epidermis) and induces epithelial development. • TGF-β is a diverse family of growth factor. Many different members and subfamilies are within it. TGF-β is a protein that controls proliferation, cellular differentiation, and other functions in most cells. • It is a type of cytokine which plays a role in immunity, cancer, bronchial asthma, heart disease, diabetes, Marfan syndrome, etc
- 3. • In humanTGF-β exist in 3 subtypes. They are TGF-β1, TGF-β2 and TGF-β3 which upregulates Marfan syndrome
- 4. STRUCTURE OF TGFβ CrystalStructure of TGF-beta 1 Crystal Structure of TGF-beta 2 Crystal Structure of TGF-beta 3 Structure of TGF-β consists of 3 domains. 1. N-terminal domain which associate with the precursor molecule to proper cellular secretory pathways 2. Peptide domain which support folding or dimerization of mature cytokine 3. C-terminal domain which are approximately 100-114 amino acid long, they help autocrine signaling molecule which is highly conserved across the superfamily.
- 5. TGFβ ACTIVATION • Somecurrently known factors which activates TGF-β are Protease, Integrins, PH and oxygen reactive species (ROS) • Disruption of these activating factors can leads to unregulated TGF-β signaling levels that may cause several complications including inflammation, autoimmune disorders, fibrosis, cancer and cataracts. • In most cases activated TGF-β ligand will initiate TGF-β signaling cascade as long as TGF receptors I and II are within reach. This is due to high affinity between TGF-β and its receptors.
- 6. TGFβ Activation continued..... LATENTTGFβ COMPLEX • TGF-β1, TGF-β2 and TGF-β3 are synthesized as Precursor molecule which contains propeptide region in addition to TGF-β homodimer. • After synthesized TGF-β homodimer interact with Latency Associated Peptide (LAP). [LAP is a protein derived from N-terminal region of TGF-β gene product]. • Interaction of TGF-β homodimer with LAP forms Small Latent Complex (SLC) • This complex remains in cell unit is bounded by another protein called Latent TGF-β Binding Protein (LTBP) forming large complex called Large Latent Complex (LLC) • It is LLC that get secreted to Extracellular Matrix (ECM)
- 8. TGFβ Activation continued..... LatentTGFβ Complex continued..... • In most cases before LLC is secreted, TGF-β precursor is cleaved from propeptide but remains attached to it by non-covalent bonds . • After its secretion it remains in ECM as inactive complex containing both LTBP and LAP which needs to be further processed to release active TGF-β. • The attachment of TGF-β to LTBT is by disulphide bond which allow it to remain inactive by preventing it from binding to its receptors. • Because of different cellular mechanism require distinct levels of TGF-β signaling, the inactive complex of this cytokine gives opportunity for proper mediation of TGF-β signaling.
- 10. INTEGRIN DEPENDENT TGFβACTIVATION TGFβ Activation continued..... 1. ACTIVATION BY PROTEASE AND METALLOPROTEASE • Plasmin and no. of Matrix Metalloprotease (MMP) play a key role in promoting tumor invasion and tissue remodeling by inducing proteolysis of several ECM components. • TGF-β activation process involves release of LLC from matrix, followed by proteolysis of LAP to release TGF-β to its receptors • MMP9 and MMP2 are known to cleave TGF-β • LAP complex contains protease sensitive hinge region which can be target for liberation of TGF-β. Despite the fact that MMP plays a key role in activating TGF-β, mice with mutation in MMP9 and MMP2 gene can still activate TGF-β and do not show any TGF-β deficiency phenotypes. It may be due to unknown proteases.
- 11. TGFβ Activation continued..... IntegrindependentTGFβ activation continued..... 2. ACTIVATION BY PH • Acidic condition can denature the LAP. • Treatment of medium with extremes of pH (1.5 or 12) result in activation of TGF-β as shown by radio receptor assays. • Mild acidic treatment (pH 4.5) yielded only 20-30% of the competition achieved by pH 1.5 3. ACTIVATION BY REACTIVE OXYGEN SPECIES (ROS) • LAP structure is important to maintain its function • Structure modification of LAP leads to disturbing the interaction between LAP and TGF-β and thus activates it. • Factors that may cause this modification may include hydroxyl radicals from ROS. TGF-β was rapidly activated after in vivo radiation exposure ROS
- 12. Fig: The constructionand extracellular activation of latent TGF-β1. The TGF-β1 dimer is synthesized intracellularly and combines with LAP to form a latent precursor (SLC). The SLC then forms a LLC with LTBP-1 via covalent bonds. The hollow arrows show the activating sites of TGF-β1. Proteases and integrins can activate latent TGF-β1 via direct proteolytic cleavage and/or by inducing a conformational change in LAP.
- 13. TGFβ SIGNALING PATHWAY MECHANISM Ligandbinding Receptor recruitment and phosphorylation SMAD phosphorylation Co-SMAD binding Transcription
- 15. TGFβ SIGNALING PATHWAY •TGF-β signaling pathway begins with a TGF-β dimer binding to Type II TGF-β receptor at cell surface. • TGF-β dimer induce formation of complex between type II and type I TGF-β receptors, both of which are transmembrane serine/threonine kinases. • Once TGF-β dimer binds to type II receptor, type II receptor phosphorelates and activates type I receptor. • The activated type I receptor phosphorelates a receptor regulated Smad (R-smad) which then dimerizes with a Co-smad. • The smad dimer translocates into the nucleus and with a DNA binding partner activates transcription of target genes.
- 19. BIBLIOGRAPHY • http://en.wikipedia.org • http://www.sinobiological.com/TGF-beta-Structure-and- Function-a-5894.html •http://maptest.rutgers.edu/drupal/?q=node/131 • http://www.karger.com/Article/FullText/338799 • http://jkweb.berkeley.edu/external/pdb/2001/tgf_beta_R1/sig naling_schematic.jpg • http://bcs.whfreeman.com/lodish5e/content/cat_010/14010- 01.htm?v=category&i=14010.01&s=00010&n=14000&o=00PRS