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TGF beta Activation

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Transforming growth factor beta (TGF-βべーた) is a potent cell regulatory polypeptide homodimer of 25kD.[1] It is a multifunctional signaling molecule with more than 40 related family members. TGF-βべーた plays a role in a wide array of cellular processes including early embryonic development, cell growth, differentiation, motility, and apoptosis.[2]

TGF-βべーた activation

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Although TGF-βべーた is important in regulating crucial cellular activities, only few TGF beta signaling pathway activations are currently known, and yet, the full mechanism behind the suggested activation pathways is not well understood. Some of the known activating pathways are cell or tissue specific, while some are seen in multiple cell types and tissues.[3][4] Proteases, integrins, pH, and reactive oxygen species are just few of the currently known factors that can activate TGF-βべーた.[5][6][7] It is well known that perturbations of these activating factors can lead to unregulated TGF-βべーた signaling levels that may cause several complications including inflammation, autoimmune disorders, fibrosis, cancer and cataracts.[8][9] In most cases an activated TGF-βべーた ligand will initiate the TGF-βべーた signaling cascade as long as TGF-βべーた receptors I and II are within reach, this is due to high affinity between TGF-βべーた and its receptors, suggesting why the TGF-βべーた signaling recruits a latency system to mediates its signaling.[3]

TGF-βべーた latency (latent TGF-βべーた complex)

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All three TGFβべーた1, TGFβべーた2 and TGFβべーた3. are synthesized as precursor molecules containing a propeptide region in addition to the TGF-βべーた homodimer.[10] After it is synthesized, the TGF-βべーた homodimer interact with a Latency Associated Peptide (LAP)[a protein derived from the N-terminal region of the TGF beta gene product] forming a complex called Small Latent Complex (SLC). This complex remains in the cell until it is bound by another protein called Latent TGF-βべーた-Binding Protein (LTBP), forming a larger complex called Large Latent Complex (LLC). It is LLC that gets secreted to the ECM.[11]

In most cases, before the LLC is secreted, the TGF-βべーた precursor is cleaved from the propeptide but remains attached to it by noncovalent bonds.[12] After its secretion, it remains in the extracellular matrix as an inactivated complex containing both the LTBP and the LAP which need to be further processed in order to release active TGF-βべーた.[3] The attachment of TGF-βべーた to the LTBP is by disulfide bond which allows it to remain inactive by preventing it from binding to its receptors. Because different cellular mechanisms require distinct levels of TGF-βべーた signaling, the inactive complex of this cytokine gives opportunity for a proper mediation of TGF-βべーた signaling.[3]

There are four different LTBP isoforms known, LTBP-1, LTBP-2, LTBP-3 and LTBP-4.[13] Mutation or alteration of LAP or LTBP can result in improper TGF-βべーた signaling. Mice lacking LTBP-3 or LTBP-4 demonstrate phenotypes consistent with phenotypes seen in mice with altered TGF-βべーた signaling.[14] Furthermore, specific LTBP isoforms have a propensity to associate with specific TGF-βべーた isoforms. For example, LTBP-4 is reported to bind only to TGF-βべーた1,[15] thus, mutation in LTBP-4 can lead to TGF-βべーた associated complications which are specific to tissues that predominantly involves TGF-βべーた1. Moreover, the structural differences within the LTBP’s provide different latent TGF-βべーた complexes which are selective but to specific stimuli generated by specific activators.

Integrin-independent TGF-βべーた activation

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  • Activation by protease and metalloprotease

Plasmin and a number of Matrix metalloproteinases (MMP) play a key role in promoting tumor invasion and tissue remodeling by inducing proteolysis of several ECM components.[5] The TGF-βべーた activation process involves the release of the LLC from the matrix, followed by further proteolysis of the LAP to release TGF-βべーた to its receptors. MMP-9 and MMP-2 are known to cleave latent TGF-βべーた.[8] The LAP complex contains a protease-sensitive hinge region which can be the potential target for this liberation of TGF-βべーた.[9] Despite the fact that MMPs have been proven to play a key role in activating TGF-βべーた, mice with mutations in MMP-9 and MMP-2 genes can still activate TGF-βべーた and do not show any TGF-βべーた deficiency phenotypes, this may reflect redundancy among the activating enzymes[3] suggesting that other unknown proteases might be involved.

  • Activation by pH

Acidic conditions can denature the LAP. Treatment of the medium with extremes of pH (1.5 or 12) resulted in significant activation of TGF beta as shown by radio-receptor assays, while mild acid treatment (pH 4.5) yielded only 20-30% of the competition achieved by pH 1.5.[16]

  • Activation reactive oxygen species (ROS)

The LAP structure is important to maintain its function. Structure modification of the LAP can lead to disturbing the interaction between LAP and TGF-βべーた and thus activating it. Factors that may cause such modification may include hydroxyl radicals from reactive oxygen species (ROS). TGF-βべーた was rapidly activated after in vivo radiation exposure ROS.[6]

  • Activation by thrombospondin-1

Thrombospondin-1 (TSP-1) is a matricellular glycoprotein found in plasma of healthy patients with levels in the range of 50–250 ng/ml.[17] TSP-1 levels are known to increase in response to injury and during development.[18] TSP-1 activates latent TGF-beta [19] by forming direct interactions with the latent TGF-βべーた complex and induces a conformational rearrangement preventing it from binding to the matured TGF-βべーた.[20]

Activation by Alpha(V) containing integrins

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The general theme of integrins to participate in latent TGF-βべーた1 activation, arose from studies that examined mutations/knockouts of βべーた6 integrin,[21] αあるふぁV integrin,[22] βべーた8 integrin and in LAP. These mutations produced phenotypes that were similar to phenotypes seen in TGF-βべーた1 knockout mice.[23] Currently there are two proposed models of how αあるふぁV containing integrins can activate latent TGF-βべーた1; the first proposed model is by inducing conformational change to the latent TGF-βべーた1 complex and hence releasing the active TGF-βべーた1 and the second model is by a protease-dependent mechanism.[24][25]

  • Conformation change mechanism pathway (without proteolysis)

αあるふぁVβべーた6 integrin was the first integrin to be identified as TGF-βべーた1 activator.[3] LAPs contain an RGD motif which is recognized by vast majority of αあるふぁV containing integrins,[26] and αあるふぁVβべーた6 integrin can activate TGF-βべーた1 by binding to the RGD motif present in LAP-βべーた1 and LAP-βべーた 3.[27] Upon binding, it induces adhesion-mediated cell forces that are translated into biochemical signals which can lead to liberation/activation of TGFb from its latent complex.[28] This pathway has been demonstrated for activation of TGF-βべーた in epithelial cells and does not associate MMPs.[29]

  • Integrin protease-dependent activation mechanism

Because MMP-2 and MMP-9 can activate TGF-βべーた through proteolytic degradation of the latent TGF beta complex,[8] αあるふぁV containing integrins activates TGF-βべーた1 by creating a close connection between the latent TGF-βべーた complex and MMPs. Integrins αあるふぁVβべーた6 and αあるふぁVβべーた3 are suggested to simultaneously bind the latent TGF-βべーた1 complex and proteinases, simultaneous inducing conformation changes of the LAP and sequestering proteases to close proximity. Regardless of involving MMPs, this mechanism still necessitate the association of intergrins and that makes it a non protolylic pathway.[24][30]

References

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  17. ^ Booth, W.J.; Berndt, M.C. (1987). "Thrombospondin in clinical disease states". Semin. Thromb. Hemostasis. 13 (3): 298–306. doi:10.1055/s-2007-1003505. PMID 3317840.
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  19. ^ Schultz-Cherry, S.; Murphy-Ullrich, J. E. (1993). "Thrombospondin causes activation of latent transforming growth factor- beta secreted by endothelial cells by a novel mechanism". J. Cell Biol. 122 (4): 923–932. doi:10.1083/jcb.122.4.923. PMC 2119591. PMID 8349738.
  20. ^ Murphy-Ullrich, J. E.; Poczatek, M. (2000). "Activation of latent TGF-beta by thrombospondin-1: mechanisms and physiology". Cytokine Growth Factor Rev. 11 (1–2): 59–69. doi:10.1016/s1359-6101(99)00029-5. PMID 10708953.
  21. ^ Huang, X.Z.; Wu, J.F.; Cass, D.; Erle, D.J.; Corry, D.; Young, S.G.; Farese Jr, R.V.; Sheppard, D. (1996). "Inactivation of the integrin beta 6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin". J. Cell Biol. 133 (4): 921–928. doi:10.1083/jcb.133.4.921. PMC 2120829. PMID 8666675.
  22. ^ Bader, B.L.; Rayburn, H.; Crowley, D.; Hynes, R.O. (1998). "Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins". Cell. 95 (4): 507–519. doi:10.1016/s0092-8674(00)81618-9. PMID 9827803.
  23. ^ Shull, M.M.; Ormsby, I.; Kier, A.B.; Pawlowski, S.; Diebold, R.J.; Yin, M.; Allen, R.; Sidman, C.; Proetzel, G.; Calvin, D.; Annunziata, N.; Doetschman, T. (1992). "Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease". Nature. 359 (6397): 693–699. Bibcode:1992Natur.359..693S. doi:10.1038/359693a0. PMC 3889166. PMID 1436033.
  24. ^ a b Wipff, P.-J.; Hinz, B. (2008). "Integrins and the activation of latent transforming growth factor [beta]1 - An intimate relationship". European Journal of Cell Biology. 87 (8–9): 601–615. doi:10.1016/j.ejcb.2008.01.012. PMID 18342983.
  25. ^ Mamuya, F. A.; Duncan, M. K. (2012). "Alpha V integrins and TGF-beta-induced EMT: a circle of regulation". J Cell Mol Med. 16 (3): 445–55. doi:10.1111/j.1582-4934.2011.01419.x. PMC 3290750. PMID 21883891.
  26. ^ Munger, J.S.; Harpel, J.G.; Giancotti, F.G.; Rifkin, D.B. (1998). "Interactions between growth factors and integrins: latent forms of transforming growth factor-βべーた are ligands for the integrin αあるふぁvβべーた1". Mol. Biol. Cell. 9 (9): 2627–2638. doi:10.1091/mbc.9.9.2627. PMC 25536. PMID 9725916.
  27. ^ Munger, J. S.; Huang, X.; Kawakatsu, H.; Griffiths, M. J.; Dalton, S. L.; Wu, J.; Pittet, J. F.; Kaminski, N.; Garat, C.; Matthay, M. A.; et al. (1999). "The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis". Cell. 96 (3): 319–328. doi:10.1016/S0092-8674(00)80545-0. PMID 10025398.
  28. ^ Kulkarni, A. B., Huh, C. G., Becker, D., Geiser, A., Lyght, M., Flanders, K. C., Roberts, A. B., Sporn, M. B., Ward, J. M., Karlsson, S. (1993) Transforming growth factor βべーた 1 null mutation in mice causes
  29. ^ Taylor, Andrew W. (2009). "Review of the activation of TGF-βべーた in immunity". Journal of Leukocyte Biology. 85 (1): 29–33. doi:10.1189/jlb.0708415. PMC 3188956. PMID 18818372.
  30. ^ Mu, D.; Cambier, S.; Fjellbirkeland, L.; Baron, J.L.; Munger, J.S.; Kawakatsu, H.; Sheppard, D.; Broaddus, V.C.; Nishimura, S.L. (2002). "the integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1". J. Cell Biol. 157 (3): 493–507. doi:10.1083/jcb.200109100. PMC 2173277. PMID 11970960.


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