I read from this journal: TGF-β-an excellent servant but a bad master (Kubiczkovaet al. Journal of Translational Medicine 2012,10:183)

TGF-β synthesis and activation

Mature dimeric form of TGF-β, composed of two monomers stabilized by hydrophobic interactions and disulphide bridge, initiates intracellular signaling [22]. The three TGF-βs are synthesized as pro-proteins (pro-TGF-βs) with large amino-terminal pro-domains (called latency associated proteins –LAPs), which are required for proper folding and dimerization of carboxy-terminal

growth-factor domain (mature peptide) [23]. This complex is called‘small latent complex’ (SLC). After folding and dimerization, TGF-β dimer is cleaved from its propeptides in trans-Golgi apparatus by furin type enzymes; however, it remains associated with its pro-peptide through noncovalent interactions, creating ‘large latent complex‘ (LLC). Most cultured cell types release latent TGF-β into extracellular matrix as LLC which in addition includes a 120–240 kDa glycoprotein called latent TGF-β binding protein (LTBP) [24]. LTBP is composed primarily of two kinds of cysteine-rich domains: EGF-like repeats (most of which are calcium-binding) and eight-cysteine domains [25]. LTBP participates in the regulation of latent TGF-β bioavailability by addressing it to the extracellular matrix (ECM) [26]. Nonactive TGF-β stays in ECM; its further activation is a critical step in the regulation of its activity (Figure 1).

A number of papers have reported TGF-β activation by retinoic acid and fibroblast growth factor-2 (FGF-2) in endothelial cells [27,28], or by endotoxin and bleomycin in macrophages [29]. Further, a variety of molecules is involved in TGF-β activation. Proteases including plasmin, matrix metaloproteases MMP-2 and MMP-9, are TGF-β activators in vitro [30,31]. Other molecules involved in the mechanism of activation are thrombospondin-1 [32], integrins, such as αVβ6orαVβ8 [33,34], or reactive oxygen species (ROS). Moreover, latent TGF-β present in conditional medium is activated by acid treatment (pH 4.5) in vitro [35]. In vivo, a similar pH is generated by osteoclasts during bone resorption. Since the bone matrix deposited by osteoblasts is rich in latent TGF-β, the acidic environment created by osteoclastsin vitro might result in latent TGF-β activation [36]

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