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Because MMP-2 and MMP-9 can activate TGF-β through proteolytic degradation of the latent TGF beta complex<ref name="yu"/>, αV containing integrins activates TGF-β1 by creating a close connection between the latent TGF-β complex and MMPs. Integrins αVβ6 and αVβ3 are suggested to simultaneously bind the latent TGF-β1 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<ref name="Wipff, P 2008"/><ref>Mu et al., 2002 D. Mu, S. Cambier, L. Fjellbirkeland, J.L. Baron, J.S. Munger, H. Kawakatsu, D. Sheppard, V.C. Broaddus and S.L. Nishimura, the integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1, J. Cell Biol. 157 (2002), pp. 493–507</ref>.
Because MMP-2 and MMP-9 can activate TGF-β through proteolytic degradation of the latent TGF beta complex<ref name="yu"/>, αV containing integrins activates TGF-β1 by creating a close connection between the latent TGF-β complex and MMPs. Integrins αVβ6 and αVβ3 are suggested to simultaneously bind the latent TGF-β1 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<ref name="Wipff, P 2008"/><ref>Mu et al., 2002 D. Mu, S. Cambier, L. Fjellbirkeland, J.L. Baron, J.S. Munger, H. Kawakatsu, D. Sheppard, V.C. Broaddus and S.L. Nishimura, the integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1, J. Cell Biol. 157 (2002), pp. 493–507</ref>.

==Disorders associated with activation of TGF-β signaling==
Upregulation of TGF-β has been documented in several inflammatory disorders. Most of these studies proposed that, restoring normal control of TGF-β signaling or inhibiting it without impairing its beneficial effects can lead to treatment of chronic inflammatory disorders as well as other TGF-β signaling associated disorders. The following are several reported diseases that are associated with activation of TGF-β by αV containing integrins that pose as potential therapeutic targets.

{| class="wikitable"
| '''Integrin''' || '''Medical condition''' || '''Experimental conclusion''' || '''ref.'''
|-
| '''α<sub>V</sub>β<sub>3</sub>''' ||1.Inflammation and fibrosis
2.Rheumatoid arthritis
|| 1. αVβ3 and αvβ5 expression induce TGFb that regulate pulmonary inflammation and fibrosis in pulmonary T lymphocytes
2. αVβ3 and TGFb plays a major role in Rheumatoid arthritis; αvβ3 as a target for treatment.
|| <ref>Irina G. Luzina,et al. "Regulation of pulmonary inflammation and fibrosis through expression of integrins alphaVbeta3 and alphaVbeta5 on pulmonary T lymphocytes." Arthritis & Rheumatism, (2009). 60(5): 1530-1539</ref>
<ref>Nam EJ et al, Up-regulated transforming growth factor beta-inducible gene h3 in rheumatoid arthritis mediates adhesion and migration of synoviocytes through alpha v beta3 integrin: Regulation by cytokines. Arthritis Rheum. 2006 Sep;54(9):2734-44</ref>
|-
| '''α<sub>V</sub>β<sub>6</sub>''' ||1.Inflammatory
2. Carcinomas

3. Fibrosis

4. Cataracts
||1. αvβ6 protect against inflammatory periodontal disease through activation of TGF-beta1

2. Blockade of integrin αvβ6 inhibits tumor progression in vivo by a transforming growth factor-beta-regulated mechanism

3. Inhibitors of alphavbeta6 integrin or TGFb for down-regulating fibrosis in the setting of acute or ongoing pulmonary, biliary injury, renal injury

4. αVβ6 is the main activator of TGF-beta1 in the lens capsule and represents a new target for PCO prevention.
|| <ref>Ghannad F, et al, Absence of alphavbeta6 integrin is linked to initiation and progression of periodontal disease. Am J Pathol. 2008 May;172(5):1271-86. Epub 2008 Apr 1</ref>
<ref>Van Aarsen LA, , et al, Antibody-mediated blockade of integrin alpha v beta 6 inhibits tumor progression in vivo by a transforming growth factor-beta-regulated mechanism. Cancer Res. 2008 Jan 15;68(2):561-70</ref>

<ref>Wang B, et al, Role of alphavbeta6 integrin in acute biliary fibrosis. Hepatology. 2007 Nov;46(5):1404-12</ref>

<ref>Horan GS et al, Partial inhibition of integrin alpha(v)beta6 prevents pulmonary fibrosis without exacerbating inflammation Am J Respir Crit Care Med. 2008 Jan 1;177(1):56-65. Epub 2007 Oct 4</ref>

<ref>Sponer Ulrike, et al, Upregulation of alphavbeta6 integrin, a potent TGF-beta1 activator, and posterior capsule opacification. Journal of cataract and refractive surgery 2005;31(3):595-606.</ref>
|-
| '''α<sub>V</sub>β<sub>8</sub>''' ||1.Inflammation

2.Autoimmunity

3.Brain hemorrhage
|| 1. Conditional loss of the TGF-beta-activating integrin αvβ8 on leukocytes causes severe inflammatory bowel
2. Loss of αvβ8 integrin on dendritic cells causes autoimmunity and colitis in mice.

3. Astrocytic αvβ8 acts as a central regulator of brain vessel homeostasis through regulation of TGF-beta activation
||<ref>Travis MA et al, Loss of integrin alpha (v)beta8 on dendritic cells causes autoimmunity and colitis in mice. Nature. 2007 Sep 20;449(7160):361-5. Epub 2007 Aug 12</ref>
<ref>Cambier S, et al, Integrin alpha (v)beta8-mediated activation of transforming growth factor-beta by perivascular astrocytes: an angiogenic control switch. Am J Pathol. 2005 Jun;166(6):1883-94</ref>
|}


==References==
==References==

Revision as of 03:18, 24 September 2010

Transforming growth factor beta (TGF-β) 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 plays a role in a wide array of cellular processes including early embryonic development, cell growth, differentiation, motility, and apoptosis[2].

TGF-β activation

Although TGF-β 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 know factors that can activate TGF-β[5][6][7]. It is well known that perturbations of these activating factors can lead to unregulated TGF-β signaling levels that may cause several complications including inflammation, autoimmune disorders, fibrosis, cancer and cataracts[8][9]. In most cases an activated TGF-β ligand will initiate the TGF-β signaling cascade as long as TGF-β receptors are I and II are within reach, this is due to high affinity between TGF-β and its receptors, suggesting why the TGF-β signaling recruits a latency system to mediates its signaling[3].

TGF-β latency (latent TGF-β complex)

All three TGFβ1, TGFβ2 and TGFβ3. are synthesized as precursor molecules containing a propeptide region in addition to the TGF-β homodimer[10]. After it is synthesized, the TGF-β 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-Binding Protein (LTBP), forming a larger complex called Large Latent Complex (LLC). It is LLC that get secreted to the ECM [11].

In most cases, before the LLC is secreted, the TGF-β 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 containg both the LTBP and the LAP which need to be further processed in order to release active TGF-β[3]. The attachment of TGF-β 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 signaling, the inactive complex of this cytokine gives opportunity for a proper mediation of TGF-β signaling[3].

There are four different LAP isoforms known, LAP-1, LAP-2, LAP-3 and LAP-4[13]. Mutation or alteration of LAP or LTBP can result to improper TGF-β signaling. Mice lacking LAP-3 or LAP-4 demonstrate phenotypes consistent to phenotypes seen in mice with altered TGF-β signaling[14]. Furthermore, specific LAP isoforms have a propensity to associate with specific TGF-β isoforms. For example, LAP-4 is reported to bind only to TGF-β1[15], thus, mutation in LAP-4 can lead to TGF-β associated complications which are specific to tissues that predominantly involves TGF-β1. Moreover, the structural differences within the LAP’s provide different latent TGF-β complexes which are selective but to specific stimuli generated by specific activators.

Integrin-independent TGF-β activation

  • 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 activation process involves the release of the LLC from the matrix, followed by further proteolysis of the LAP to release TGF-β to its receptors. MMP-9 and MMP-2 are known to cleave latent TGF-β[8]. The LAP complex contains a protease-sensitive hinge region which can be the potential target for this liberation of TGF-β[9]. Despite the fact that MMPs have been proven to play a key role in activating TGF-β, mice with mutations in MMP-9 and MMP-2 genes can still activate TGF-β and do not show any TGF-β 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 and thus activating it. Factors that may cause such modification may include hydroxyl radicals from reactive oxygen species (ROS). TGF-β 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 complex and induces a conformational rearrangement preventing it from binding to the matured TGF-β[20].

Activation by Alpha(V) containing integrins

The general theme of integrins to participate in latent TGF-β1 activation, arose from studies that examined mutations/knockouts of β6 integrin[21], αV integrin[22], β8 integrin and in LAP. Theses mutations produced phenotypes that were similar to phenotypes seen in TGF-β1 knockout mice[23]. Currently there are two proposed models of how αV containing integrins can activate latent TGF-β1; the first proposed model is by inducing conformational change to the latent TGF-β1 complex and hence releasing the active TGF-β1 and the second model is by a protease-dependent mechanism[24].

  • Conformation change mechanism pathway (without proteolysis)

αVβ6 integrin was the first integrin to be identified as TGF-β1 activator[3]. LAPs contain an RGD motif which is recognized by vast majority of αV containing integrins[25], and αVβ6 integrin can activate TGF-β1 by binding to the RGD motif present in LAP-β1 and LAP-β 3[26]. 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[27]. This pathway has been demonstrated for activation of TGF-β in epithelial cells and does not associate MMPs[28].

  • Integrin protease-dependent activation mechanism

Because MMP-2 and MMP-9 can activate TGF-β through proteolytic degradation of the latent TGF beta complex[8], αV containing integrins activates TGF-β1 by creating a close connection between the latent TGF-β complex and MMPs. Integrins αVβ6 and αVβ3 are suggested to simultaneously bind the latent TGF-β1 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][29].

References

  1. ^ Roberts, A.B. and Sporn, M.B., 1990. The transforming growth factor βs. In: Sporn, M.B. and Roberts, A.B., Editors, 1990. Peptides, Growth Factors and Their Receptors Part I, Springer-Verlag, Berlin, pp. 419–472,
  2. ^ Yue J, Mulder KM. Transforming growth factor-beta signal transduction in epithelial cells. Pharmacol Ther. 2001;91:1–34.
  3. ^ a b c d e f .J.P. Annes, J.S. Munger and D.B. Rifkin, Making sense of latent TGFβ activation, J. Cell Sci. 116 (2003), pp. 217–224.
  4. ^ P. ten Dijke and C.S. Hill, New insights into TGF-β-Smad signalling, Trends Biochem Sci 29 (2004), pp. 265–273
  5. ^ a b Stetler-Stevenson W.G., Aznavoorian S., Liotta L.A.(1993) Tumor cell interactions with the extracellular matrix duing invasion and metastasis. Annu. Rev. Cell Biol. 9:541–573
  6. ^ a b Barcellos-Hoff, M. H. and Dix, T. A. (1996). Redox-mediated activation of latent transforming growth factor-beta 1. Mol. Endocrinol. 10,1077 -1083
  7. ^ Wipff, P.-J. and B. Hinz (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.
  8. ^ a b c Yu, Q. and Stamenkovic, I. (2000). Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 14,163 -176
  9. ^ a b Taipale, J., Miyazono, K., Heldin, C. H. and Keski-Oja, J. (1994). Latent transforming growth factor-beta 1 associates to fibroblast extracellular matrix via latent TGF-beta binding protein. J. Cell Biol. 124,171 -181
  10. ^ Derynck, R., Jarrett, J. A., Chen, E. Y., Eaton, D. H., Bell, J. R., Assoian, R. K., Roberts, A. B., Sporn, M. B., Goeddel, D. V. (1985) Human transforming growth factor-β complementary DNA sequence and expression in normal and transformed cells Nature 316,701-705
  11. ^ Rifkin, D. B. (2005) Latent transforming growth factor-β (TGF-β) binding proteins: orchestrators of TGF-β availability J. Biol. Chem. 280,7409-7412
  12. ^ Dubois, C. M., Laprise, M. H., Blanchette, F., Gentry, L. E., Leduc, R. (1995) Processing of transforming growth factor β 1 precursor by human furin convertase J. Biol. Chem. 270,10618-10624
  13. ^ Saharinen, J., Hyytiäinen, M., Taipale, J. and Keski-Oja, J., 1999. Latent transforming growth factor-beta binding proteins (LTBPs) structural extracellular matrix proteins for targeting TGF-beta action. Cytokine Growth Factor Review 10, pp. 99–117
  14. ^ 6. Sterner-Kock, A., Thorey, I. S., Koli, K., Wempe, F., Otte, J., Bangsow, T., Kuhlmeier, K., Kirchner, T., Jin, S., Keski-Oja, J. et al. (2002). Disruption of the gene encoding the latent transforming growth factor-beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer. Genes Dev. 16,2264 -2273
  15. ^ Saharinen, J. and Keski-Oja, J. (2000). Specific sequence motif of 8-Cys repeats of TGF-beta binding proteins, LTBPs, creates a hydrophobic interaction surface for binding of small latent TGF-beta. Mol. Biol. Cell 11,2691 -2704
  16. ^ Lyons R. M., Keski-Oja, J. and Moses, H. L. (1988). Proteolytic activation of latent transforming growth factor-beta from fibroblast-conditioned medium. J. Cell Biol. 106,1659 -1665
  17. ^ W.J. Booth and M.C. Berndt, Thrombospondin in clinical disease states, Semin. Thromb. Hemostasis 13 (1987), p. 298
  18. ^ R.J. Raugi, J.E. Olerud and A.M. Gown, Thrombospondin in early human wound tissue. J. Invest. Dermatol. 89 (1987), pp. 551–554.
  19. ^ Schultz-Cherry, S. and 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. 122,923 -932
  20. ^ Murphy-Ullrich, J. E. and Poczatek, M. (2000). Activation of latent TGF-beta by thrombospondin-1: mechanisms and physiology. Cytokine Growth Factor Rev. 11, 59-69.
  21. ^ Huang et al., 1996 X.Z. Huang, J.F. Wu, D. Cass, D.J. Erle, D. Corry, S.G. Young, R.V. Farese Jr. and D. Sheppard, 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 (1996), pp. 921–928
  22. ^ Bader et al., 1998 B.L. Bader, H. Rayburn, D. Crowley and R.O. Hynes, Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins, Cell 95 (1998), pp. 507–519.
  23. ^ Shull et al., 1992 M.M. Shull, I. Ormsby, A.B. Kier, S. Pawlowski, R.J. Diebold, M. Yin, R. Allen, C. Sidman, G. Proetzel, D. Calvin, N. Annunziata and T. Doetschman, Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease, Nature 359 (1992), pp. 693–699.
  24. ^ a b Wipff, P.-J. and B. Hinz (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
  25. ^ Munger, J.S., J.G. Harpel, F.G. Giancotti, and D.B. Rifkin. 1998. Interactions between growth factors and integrins: latent forms of transforming growth factor-β are ligands for the integrin αvβ1. Mol. Biol. Cell. 9:2627–2638
  26. ^ 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 96,319 -328
  27. ^ 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 1 null mutation in mice causes
  28. ^ Andrew W. Taylor, Review of the activation of TGF-β in immunity, (2008) Journal of Leukocyte Biology. 2009;85:29-33.)
  29. ^ Mu et al., 2002 D. Mu, S. Cambier, L. Fjellbirkeland, J.L. Baron, J.S. Munger, H. Kawakatsu, D. Sheppard, V.C. Broaddus and S.L. Nishimura, the integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1, J. Cell Biol. 157 (2002), pp. 493–507
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