Structural Biochemistry/Transforming Growth Factor Beta

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Transforming Growth Factor Beta  [edit]


TGFβ is a cytokine, or cell-signaling protein molecule, that signals for many different cellular functions. It controls for cell growth and division, differentiation, cell death, and cell movement. TGFβ has also been associated with cancer production, immune responses, and fibrosis. When TGFβ binds to its TGFβ receptor on the cell surface, it sets off a cascade of intracellular signals that will eventually lead to alterations in specific gene expression. The trans-membrane glycoprotein betaglycan supports the receptor binding. The receptors that TGFβ attaches to are in fact serine/threonine kinase transmembrane receptors; a phosphorylation is what activates the kinase function of the side of the receptor protein within the cell. This leads to another eventual phosphorylation of Smad2 or Smad3, which are signal transducers and directly regulate gene expression. Incidentally, Smad is named such because of its similarity (homologous nature) to two other proteins, SMA and MAD, which stand for "small body size" and "mothers against decapentaplegic".[1] Smad proteins themselves can modulate other pathways that affect gene expression. In addition, TGFβ itself will activate non-Smad-mediated pathways like the mitogen-activated protein kinase.[2] The overall result is to regulate gene expression in different ways depending on the pathways used, the activation of TGFβ, and the ability of cell receptors to accept it.

The TGFβ Complex[edit]

Latent TGFβ[edit]

TGFβ is initially formed as an inactive complex that cannot bind to receptors until activated. The complex consists of two instances of latency-associated peptides and TGFβ bound together into a homodimer. In order for latent TGFβ to become active, it must be cleaved from the latency-associated peptide (LAP). The protease furin, within the Golgi, breaks the covalent bonds between LAP and TGFβ, but the two molecules remain noncovalently bonded to each other after cleavage, so there is another mechanism required to separate the two and contribute to functional TGFβ.

TGFβ activation[edit]

Several different mechanisms for TGFβ activation have been proposed in the past few decades, some of which involve pH changes, heat, the serine protease plasmin, matrix metalloproteases, and thrombospondin-1.[3] However, recent work hints towards integrin, a receptor protein, as the crucial trigger of TGFβ activation.[4] Integrins play an intricate role in the function of TGFβ. Integrins are adherent to cell-membranes and will send signals to various proteins, initiating and sustaining communication between the cytoplast and the plasma membrane. It has been proposed that in order to activate TGFβ, specific integrins bind to the complex, forcing a conformational change, and enabling interaction with other receptors. Twenty-four different integrins have been identified in mammalian cell types. In vitro, six of the twenty-four integrins bind to TGFβ. 

TGFβ-binding Integrins[edit]

Integrins αvβ3 and αvβ5 bound to TGFβ; [edit]

Although shown in vivo to have no pathway effect when removed, these integrins do function to activate TGFβ. The signaling of TGFβ appears to up-regulate the expression of these two integrins. According to mice studies, αvβ3 and αvβ5 seem to contribute to the differentiation in lung fibroblast to myofibroblasts, yet the mice lacking the integrins are not protected against fibrosis any more than normal mice. Further research is needed on these integrins to examine their presence of function.

Integrin αvβ6 bound to TGFβ ;[edit]

The activation of TGFβ via αvβ6 is related to lung and skin immune response. αvβ6 expression is found overwhelmingly in epithelial cells. When the expression of this integrin was "knocked out" from mice by giving them antibodies that blocked αvβ6 , the mice experienced inflammation of the layers of the lung and periodontal disease from oral epithelium damage. However, the mice appeared to be protected from pulmonary, liver, and renal fibrosis, confirming the integrin's effect on the differentiation of fibroblasts (and hence the lack of the integrin resulting in protection from fibrosis). Several cell carcinomas appear to up-regulate the levels of this integrin, and high levels of the integrin with cancer are linked to a worsening condition. Likely, the integrin promotes tumorgenesis in addition to the aforementioned differentiation of fibroblasts.

Integrin αvβ8 bound to TGFβ;[edit]

 The activation of TGFβ via integrin αvβ8 has been tied with cancer function, immune function, and vascular biology. αvβ8 appears to manage the neuroepithelial cells, so mice without this integrin suffered from defects in brain vascular development and died. Interestingly, unlike αvβ6, the αvβ8-mediated activation of TGFβ protects from lung cancer and controls self-harming T-cell responses. Notably, the presence of disease lesions in the brain of an organism reduce the expression of αvβ8. Brain tumor cells, in order to promote their own growth, will suppress the ability of astrocytes to induce αvβ8 expression so that angiogenesis is enhanced.

Mechanism of TGFβ Activation[edit]

Within the LAP region of the latent TGFβ-LAP complex is what is termed the RGD integrin-binding motif. This area is where the integrins target; there are two methods through which the integrins can activate the complex.

Mechanical Induction[edit]

Integrins αvβ5 and αvβ6 activate the complex not by complete cleavage of the LAP from the TGFβ molecule, but by inducing a sufficient conformational change in LAP so that TGFβ becomes able to interact with its receptor. An intact actin cytoskeleton is necessary for this mechanism; the inhibition of cell contraction results in a much lowered amount of active TGFβ, indicating that without cell contraction the conformational change is not sufficient to enable TGFβ to interact with its receptor.

Protease-mediated induction[edit]

Integrin αvβ8 does not require the actin cytoskeleton that its two fellow integrins require. It does not appear to be controlled by cell contraction, and the attachment sites do not even connect to the cytoskeleton, which indicates that actin-mediated cell contraction does not participate as for αvβ5 and αvβ6. The integrin instead releases TGFβ from LAP entirely, causing it to become active and freely functional.


  1. Sekelsky, J. J., Newfeld, S. J., Raftery, L. A., Chartoff, E. H. & Gelbart, W. M. Genetic characterization and cloning of Mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster. Genetics 139, 1347–1358 (1995).
  2. Zhang, Y. E. (2009) Non-Smad pathways in TGFβ signaling. Cell Res. 19, 128-139
  3. Shi, Y. and Massague, J. (2003) Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113, 685-700
  4. Worthington, J. J., Klementowicz, J. E., and Travis, M. A. (2011) TGFβ: a sleeping giant awoken by integrins. Trends Biochem Sci. 2011 Jan;36(1):47-54