Structural Biochemistry/TGFβ and Integrins
TGFβ The transforming growth factor beta is a protein that controls many cellular responses. TGFβ is an important multifunctional cytokine. There are three types of TGFβ: TGFβ1, TGFβ2, TGFβ3. These isoforms have similar functional properties that are non-overlapping and have distinct phenotypes. Furthermore, the forms are expressed by many different cell types and many are capable to respond to TGFβ. The TGFβ isoforms are encoded by separate genes. The protein is produced in its inactive form until integrins activate TGFβ so that it can bind to its receptor to activate the cascades of signals that result in modulation of gene transcription. There have been many different processes that have been experimented in labs to activate TGFβ such as heat, acidic pH, reactive oxygen, and proteases. It is important that TGFβ is produced in its inactive form that makes sure that TGFβ’s potent effects are only apparent during appropriate surroundings and time.
TGFβ Signaling Pathway The activated TGFβ binds to TGFβRII. Then, TGFβII phosphorylates TGFβRI to activate the cytoplasmic domain’s kinase activity. This create TGFβ-ligated tetrameric receptor complex. The activated cytoplasmic domain phosphorylates Smad2 or Smad3. Then, the phosphorylated Smad2/3 complex binds to Smad4 and migrates to the nucleus. Next, the Smad2/3/4 complex binds to Smad-responsive elements. This can either start gene transcription or repress it. This pathway can be inhibited by Smad7 by competing with Smad2/3 to bind to TGFβ. In addition, other pathways that TGFβ can start are MAPK, Wnt, Notch, and PI3K.
Integrins – Activators of TGFβ Integrins are large family of cell adhesion and signaling receptors. There are two subunits, α and β, that bind together to form a heterodimeric type 1 transmembrane receptor. There are six types of integrins: αvβ1, αvβ3, αvβ6, αvβ8, α8β1. The αvβ3 and αvβ5 integrins activates TGFβ in fibroblastic cells. Research in mice with defective αvβ3 and αvβ5 show that autoimmune disease scleroderma disease. Increased expression of these integrins resulted in lung fibroblast-to-myofibroblast differentiation that plays a role in pulmonary fibrosis. On the other hand, integrin αvβ6 is usually expressed in the epithelial cells. In research, mice that do not express αvβ6 show signs of mild inflammatory phenotype to the skin and lungs. This shows that the αvβ6 helps with skin and lung cells in controlling immune homeostasis. Integrin αvβ8 is the integrin that is expressed in the most cell types. Mice that do not have αvβ8 do have αvβ8 complex with transforming growth factor beta, that results brain disease. Other problems that these mice would have are cleft palate and chronic pulmonary disease. Thus, the results show that αvβ8 complex with TGFβ is important in controlling neurovascular development. More results that the complex influences homeostasis in the immune system.
TGFβ Activation with Integrins TGFβ is activated by integrins by protease-independent and dependent mechanisms. In order for TGFβ to bind to its receptors, the protein has to change its shape in order to not be masked by LAP. The latent TGFβ complex binds to ECM by interacting with integrin αvβ3 or αvβ5 receptors . This will cause the TGFβ protein to change its shape. Then, αvβ8 bind to latent TGFβ that will result in the cleavage of LAP and release of active TGFβ to send signals to other cells.
References Worthington, John J., Joanna E. Klementowicz, and Mark A. Travis. "TGFβ: A Sleeping Giant Awoken by Integrins." Trends in Biochemical Sciences (2010): n. pag. Print.