An artificial tether (anti-HA; triangles) activates just as well as LTBP.

The extracellular matrix (ECM) acts as a storage facility for tons of factors waiting to do business in the cell. Annes et al. (page 723) show that the ECM anchoring of one factor, the cytokine TGF-β, is essential for its activation. The anchoring may give cells something to pull against, with the pulling mediating the activation.

Most TGF-β is secreted as a complex containing TGF-β, a TGF-β pro-domain, and a protein called the latent TGF-β binding protein (LTBP). By the time the complex is extracellular, the pro-domain has been cleaved from TGF-β but remains noncovalently bound to TGF-β and covalently linked (via disulfides) to LTBP. The pro-domain stops TGF-β from signaling, but the complex can be activated in the presence of cells expressing the integrin αVβ6.

The mechanism of TGF-β activation remained a mystery. The authors first established that TGF-β plus its TGF-β pro-domain could not be activated by αVβ6 in the absence of LTBP. Furthermore, LTBP's known binding to the pro-domain was not enough. A second domain of LTBP, called the hinge domain, was also needed for activation. This is the same domain required for LTBP binding to ECM, and its function could be replaced by another anchoring mechanism: surface-coated antibodies targeted against an unrelated LTBP epitope.

Thus, the function of LTBP may be in part to anchor latent TGF-β in the ECM. But for activation, the authors speculate that this anchoring also gives the cell something to pull against. Only when integrin-mediated pulling meets resistance (because the integrin on the cell binds to TGF-β, and the TGF-β binds to the ECM-anchored LTBP) would the pro-domain be released. Activation would fail if any link was broken: if the cell was expressing an integrin that does not bind to TGF-β; the LTBP isoform did not bind to the ECM; or a protease separated the TGF-β–binding and ECM-binding domains of LTBP. All these variations would limit the activation of this extremely potent cytokine. ▪