ReviewBiochemistry

Specificity, versatility, and control of TGF-β family signaling

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Science Signaling  26 Feb 2019:
Vol. 12, Issue 570, eaav5183
DOI: 10.1126/scisignal.aav5183

Figures

  • Fig. 1 Ligand processing and presentation.

    (A) TGF-β family proteins are synthesized as precursor molecules consisting of a signal peptide, a prodomain (termed latency-associated polypeptide, for TGF-β), and the mature polypeptide. After signal peptide removal, the precursor is further processed by proteolytic cleavage at basic residues, thus separating the prodomain from the mature polypeptide, which remain noncovalently associated. Concomitant, disulfide-linked dimerization of the mature polypeptides then forms mature homodimeric and heterodimeric complexes, as shown. (B) Latent TGF-β complex can associate through disulfide bonding with latent TGF-β binding protein (LTBP) into a large latent complex (LLC) that, in turn, associates with the ECM (top), or with the plasma membrane-associated glycoprotein-A repetitions predominant (GARP; bottom). (C) Cytoneme-associated activation of TGF-β family signaling is depicted. Long cytonemes extend from the cell body and present TGF-β family receptors to ligand complexes. Binding of ligand to the receptors results in activation of the type I receptors (medium to dark gray) by the type II receptors (light gray).

    CREDIT: VERONICA FALCONIERI HAYS/SCIENCE SIGNALING
  • Fig. 2 Posttranslational and functional modifications of the glycosylated TGF-β receptors TβRII and TβRI before or after ligand-induced activation.

    AKT activation in response to insulin or other stimuli drives TGF-β receptor transport from intracellular compartments to the cell surface (middle). Without activation (left), the plasma membrane–associated TβRI receptor (medium gray) can undergo tumor necrosis factor–α converting enzyme (TACE)–mediated ectodomain cleavage, thus preventing ligand-induced activation of signaling, or the receptor complex can undergo polyubiquitylation that leads to receptor degradation. Ligand-induced activation of the TβRI receptor (middle, moving right) results in phosphorylation (P) of its GS domain by the TβRII receptor (lightest gray), and phosphorylation of TβRII and TβRI leads to (right) TβRII neddylation (N), TβRI sumoylation (SUMO), and TβRII and TβRI ubiquitylation (U). Activation of the TβRI receptor may also result in proteolytic release of its intracellular cytoplasmic domain (ICD) by presenilin-1 after TACE-mediated ectodomain cleavage and subsequent nuclear translocation of the ICD.

    CREDIT: VERONICA FALCONIERI HAYS/SCIENCE SIGNALING
  • Fig. 3 Roles of coreceptors in TGF-β family ligand binding to heteromeric complexes of type II and type I receptors.

    Membrane-anchored coreceptors (blue) are generally present as dimers with type II receptors (light gray) at the cell surface and can promote ligand binding to the receptors (top row), as reported for betaglycan, which enhances binding of TGF-β2 to the TGF-β receptors, and crypto, which enables nodal binding to activin receptors and subsequent nodal signaling. Alternatively, coreceptor interaction can interfere with the formation of complexes between type II (light gray) and type I (dark gray) receptors (second row), as reported for RGMs as BMP coreceptors. Coreceptors can also be cleaved at the cell surface, resulting in the release of their ectodomains, which retain their affinity for ligand, resulting in ligand sequestration and repression of signaling activation (third row), as reported for betaglycan and endoglin. Coreceptors also provide opportunities to coordinate activation of distinct signaling pathways (bottom), as also reported for betaglycan, which can bind bFGF (white oval) in addition to TGF-β and coordinately regulate FGF receptor (pink) and TGF-β receptor signaling.

    CREDIT: VERONICA FALCONIERI HAYS/SCIENCE SIGNALING
  • Fig. 4 Schematic comparison of the simplified structures of R-Smads (Smad1, Smad2, Smad3, Smad5, and Smad8), Smad4, and inhibitory Smads (Smad6 and Smad7).

    The R-Smads and Smad4 have two conserved domains, the MH1 (peach) and MH2 (red) domains, separated by a variable serine- and proline-rich linker region (white). The linker region is targeted for phosphorylation (P) by various signaling kinases that, thus, control the stabilities and functions of the Smads. A β-hairpin (β-hp), which in Smad2 is interrupted by a sequence encoded by exon 3 (ex 3) but is maintained in Smad2β, i.e., the Smad2Δex3 variant, enables MH1 domain binding to DNA. The inhibitory Smads lack an MH1 domain and have a long and variable sequence (pink) preceding the MH2 domain. This sequence is thought to be structurally versatile depending on posttranslational modifications and protein interactions. The positively charged L3 loop in the MH2 domain mediates association with the activated type I receptors and with other Smads. The R-Smads, but not Smad4 and the inhibitory Smads, have a conserved C-terminal SXS motif that is phosphorylated by the activated type I receptor, resulting in R-Smad activation.

    CREDIT: VERONICA FALCONIERI HAYS/SCIENCE SIGNALING
  • Fig. 5 Smad-dependent regulation of gene expression.

    (A) Simplified model of TGF-β–induced R-Smad activation leading to Smad-mediated activation of gene expression. Signaling is initiated by TGF-β binding to a heteromeric complex of type II (light gray) and type I (dark gray) receptors, resulting in activation of the type I receptors (darkest gray) and C-terminal R-Smad phosphorylation. The activated R-Smads dissociate from the type I receptors, forming a complex with Smad4, and the R-Smad-Smad4 complexes translocate into the nucleus, where they regulate gene expression with transcription factors (TF) and coregulators. Inhibitory Smads (Smad6 and Smad7) interfere with functional Smad activation, by associating with type I receptors, thus preventing R-Smad activation, or by interfering with the complex formation of R-Smads with Smad4. Activated R-Smad-Smad4 complexes associate and cooperate with high-affinity DNA binding transcription factors to either activate or repress the transcription of genes into mRNA or microRNA (miRNA) precursors. (B) Activated R-Smad-Smad4 complexes recruit histone-modifying enzymes, resulting in chromatin remodeling. Recruitment of the acetyltransferase p300, which commonly acts as transcription coactivator for Smad complexes, confers H3K9 acetylation, whereas recruitment of the methyltransferase SETDB1 induces H3K9 methylation and thus represses transcription. Smad-mediated recruitment of histone deacetylases leads to histone deacetylation. (C) TGF-β–activated Smad complexes regulate mRNA splicing in association with hnRNPE1. (D) Activated R-Smads direct miRNA processing through association with the p68 RNA helicase in complex with Drosha ribonuclease (RNAse). (E) Activated Smad2 or Smad3 can associate with m6A methyltransferase complexes to promote methylation of mRNA.

    CREDIT: VERONICA FALCONIERI HAYS/SCIENCE SIGNALING
  • Fig. 6 Signaling cross-talk through posttranslational control of Smad activation and functions.

    R-Smad association with the receptors (“I”) is controlled by inhibitory Smad6 and/or Smad7, which prevents R-Smad access to the activated type I receptors (dark gray). In addition, upon activation in response to various signaling pathways, AKT and IRF3 bind to Smad3 and thus attenuate Smad3 binding to activated type I receptors. Various signaling pathways that act through kinases target the linker regions of R-Smads for phosphorylation (“II”), with the possibility for further regulation by subsequent dephosphorylation, and thus control the subcellular localization, stability, and function of Smads. Smads can also be polyubiquitylated, leading to degradation, and in some cases targeted linker phosphorylation is a prerequisite for subsequent polyubiquitylation and degradation. Some kinases and a phosphatase are listed as examples. In the nucleus (“III”), phosphorylation and dephosphorylation by kinases and phosphatases further regulate the Smad activities. Direct transcriptional activation or repression of target genes requires association of Smad complexes with DNA binding transcription factors (TF) and coregulators (“IV”). Smads have been shown to associate with a wide variety of transcription factors, depending on the signaling status of the cells and the targeted gene. Extensive signaling cross-talk occurs at the level of Smad complex association with DNA binding transcription factors, because they are also regulated by phosphorylation or other modifications in response to signaling pathways. Some examples are listed. Such cross-talk may occur before binding of Smad–transcription factor complexes to regulatory gene sequences or after formation of the DNA binding nucleoprotein complexes. JAK, Janus kinases; GSK3, glycogen synthase kinase; PKC, protein kinase C; CAMKII, calcium/calmodulin-dependent protein kinase II; SCP, small C-terminal domain phosphatase; ROCK, Rho-associated protein kinase; PPM1A, protein phosphatase Mg2+/Mn2+ dependent 1A.

    CREDIT: VERONICA FALCONIERI HAYS/SCIENCE SIGNALING
  • Fig. 7 TGF-β receptors activate Smad signaling and non-Smad signal transduction pathways.

    Smad-mediated signaling occurs in association with nascent clathrin-dependent endosomal compartments (left), whereas receptor-induced non-Smad signaling pathways emanate from caveolar compartments (right) or are not yet known to associate with either type of compartment. TGF-β–induced ERK pathway activation occurs in caveolar lipid raft compartments and requires ShcA. TGF-β–induced PI3K-AKT signaling has also been shown to emanate from caveolar lipid raft compartments and to require ShcA, raising the possibility that both pathways initiate from the same receptor complexes. However, TGF-β–induced AKT activation was also shown in different cells to require TRAF6 and to not require the kinase activity of TβRI, suggesting that it initiates from different receptor complexes, as shown. TGF-β–induced p38 MAPK and c-Jun N-terminal kinase (JNK) activation has been shown to require TRAF6 and to be initiated by TAK1 (TGF-β–activated kinase, also known as MAP3K7) activation, whereas TGF-β–induced p38 MAPK activation has been localized to cholesterol-rich lipid raft compartments, suggesting the existence of distinct complexes for TGF-β–induced p38 MAPK, JNK, and nuclear factor κB (NFκB) signaling, as shown. Whether Smad7 association with the type I receptor facilitates, is required for, or antagonizes TGF-β–induced p38 MAPK activation is unclear because of seemingly conflicting reports.

    CREDIT: VERONICA FALCONIERI HAYS/SCIENCE SIGNALING

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