The TGF-β family comprises
TGFB1,
TGFB2, and
TGFB3. All three genes are highly conserved across species and humans, in which their products share strong sequence similarity and also display nearly identical three-dimensional structures
[8][9]. They signal through the same ubiquitously expressed transmembrane receptors, generally referred to as TβRI and TβRII, which develop a similar affinity for isoforms TGF-β1 and TGF-β3, whereas only TβRII binds with less intensity to TGF-β2
[10][11]. Thus far, the main element discriminating physiological roles for the three TGF-β isoforms might be differences in their spatial and temporal expression patterns. However, molecular recognition of TGF-β is not achieved via simple ligand–receptor interaction, but through a network of interactions deeply affecting the final outcome. For starters, TGF-β is usually regarded as a homodimer, yet heterodimeric configurations showing variable potency and binding affinity with TβRs have been also reported both in vivo and in vitro
[12][13]. Once secreted, TGF-β can remain in a latent state for some time, allowing for stock build-up in the extracellular matrix (ECM). This arises from the presence of the latency associated peptide prodomain (LAP). Indeed, TGF-β is translated into single polypeptide chains containing both a monomer and its corresponding LAP whose maturation through the trans-Golgi network involves the formation of disulfide bonds resulting in dimer stabilization. The following proteolytic cleavage splits polypeptide chains; however, the association between LAP and TGF-β remains stable through non-covalent interaction. LAP removal constitutes a critical regulatory event for TGF-β activity achieved through diverse mechanisms, which range from conformational changes promoted by interaction with integrins to enzymatic digestion including matrix metalloproteinases
[14][15]. In that sense, and in contrast to TGF-β isoforms, LAPs show four times greater sequence divergence, allowing for diversification of the activation dynamics
[5]. Additionally, modulators already present on secretion, such as latent TGF-β binding proteins (LTBPs), or in the ECM, such as decorin, biglycan, or fibromodulin, bind and delay TGF-β activation
[16][17]. Moreover, co-receptor molecules with the ability to modulate and which bind to TβRs have been described
[18]. Furthermore, downstream to TβRs activation, intracellular transduction of the signal shows, again, possibilities for modulation by means of post-translational modifications
[19][20] or the regulation of protein levels of the factors participating on either Smad-reliant canonical signaling
[21] or MAP-kinase-dependent non-canonical signaling
[22]. In that sense, the aspects of TGF-β signaling intracellular transduction and the crosstalk with other pathways have been the subject of extensive reviews
[23][24][25][26]. In the end, the ability of TGF-β stimulation to promote long-term modulation of gene expression is affected by concomitant circumstances, for instance, the epigenetic status or the microRNA profile of the targeted cell
[27][28], among others. Altogether, the sum of mechanisms involved in TGF-β signaling implies countless possibilities for modulation at any level, making the final outcome highly dependent on cell type and context. This fact encourages the shift of the paradigm for TGF-β pathway from linear non-amplified signaling cascades to complex signaling networks, better explaining the variety of functional responses to TGF-β isoforms
[5].