The genes associated with TGF-beta isoforms encode 390-412 amino acids-long precursor proteins constituting three distinct domains: a N-terminal signal domain which associates the full precursor molecule to the proper cellular secretory pathways; a propeptide domain, which may support folding or dimerization of the mature cytokine; and an approximately 100-114 amino acids-long C-terminal "TGF-beta-like" domain - the functional autocrine signaling molecule - which is highly conserved across the superfamily. The secreted precursors are proteolytically processed in the Golgi apparatus, which then releases the mature C-terminal protein fragment as a disulfide-bonded homodimer, which is constituted by two identical subunits linked by four internal disulfide bonds and a single cross-linking disulfide bond, and is further stabilized by hydrophobic effects. Structurally, each monomer of the dimer pair is comprised of several β strands.
The three isoforms of TGF-beta currently recognized were first identified from three peaks of activity seen during some of the earliest attempts to purify TGF-beta. The N-linked glycosylation sites, nine cysteine residues, the hydrophobic dimer interface and the protein backbone are highly conserved features across all three isoforms. However, the chromosomal location of the gene associated with each isoform is distinct. In humans, the TGF-beta1 gene is located at 19q13; the TGF-beta2 gene at 1q41; and the TGF-beta3 gene at 14q23-4.
TGF-beta family members play central roles in metazoan developmental processes, including initiation of appendage formation in adult flies, establishment of the mammalian left-right body plane, and regulation of nematode morphology. TGF-beta signaling is initiated through highly specific binding and complex formation between the active ligand molecule and its corresponding cell surface receptors. The TGF-beta receptors, types I and II, are serine/threonine kinases and are brought into proximity such that the TGF-beta receptor II phosphorylates the receptor I kinase domain, which subsequently phosphorylates R-Smad proteins - members of the Smad tumor suppressing protein family. Once phosphorylated, R-Smad proteins undergo homotrimerization to form heteromeric oligomer complexes with the Co-Smad protein, Smad4. Once in the nucleus, these Smad complexes regulate target gene transcription. This regulation is not explicit or rigid, but rather variable depending on the cell's genetic status, functional identity, environmental constraints, and concurrent signaling, which collectively determine the specific genes affected and the outputs modulated
During human development, homeostasis is maintained across the embryo's rapidly expanding networks of tissues and organ systems through carefully balanced molecular signaling pathways. For example, bone morphogenic protein-4 (BMP4), a member of the superfamily, is active during early inner cell mass proliferation, and later in development among neural, bone and dermal cell types. Other family members are involved in left-right axis symmetry and asymmetry formation, vascular development, and in cardiac, lung, craniofacial, and urogenital development. Mutations in these critical TGF-beta systems, whether in the genes encoding the cytokines, their receptors, or members of the downstream intercellular signaling pathways, are responsible for a wide spectrum of developmental disorders, as well as many adult disease states .
TGF-beta signaling not only acts as a tumor suppressor, but has been shown, in vitro and in vivo, to act as a powerful stimulator of tumor progression. More about TGF-beta and cancer.
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