Transforming growth factor β (TGF-β) and related growth factors are secreted pleiotropic factors that play critical roles in embryogenesis and adult tissue homeostasis by regulating cell proliferation, differentiation, death, and migration. The TGF-β family members signal via heteromeric complexes of type I and type II receptors, which activate members of the Smad family of signal transducers. The main attribute of the TGF-β signaling pathway is context-dependence. Depending on the concentration and type of ligand, target tissue, and developmental stage, TGF-β family members transmit distinct signals. Deregulation of TGF-β signaling contributes to developmental defects and human diseases. More than a decade of studies have revealed the framework by which TGF-βs encode a context-dependent signal, which includes various positive and negative modifiers of the principal elements of the signaling pathway, the receptors, and the Smad proteins. In this review, we first introduce some basic components of the TGF-β signaling pathways and their actions, and then discuss posttranslational modifications and modulatory partners that modify the outcome of the signaling and contribute to its context-dependence, including small noncoding RNAs.

/pdf/tgf-b-signaling-from-receptors-to-smads-51r7lplg5s.pdf

TGF-β Signaling from Receptors to Smads.

Transforming growth factor (TGF)-b is a pleiotropic cytokine regulating a variety of cellular processes such as cell growth, differentiation, apoptosis, migration, cell adhesion, and immune response. In the well-understood classical TGF-b signaling pathway, TGF-b activates Smad signalling via its two cell surface receptors such as TbRII and ALK5/TbRI, leading to Smad-mediated transcriptional regulation. In addition, TGF-b may also activate other signaling pathways like mitogen-activated protein kinase, PI3K, etc. The signaling of TGF-b is finely regulated at different levels. Inhibitory Smads, including Smad6 and Smad7, are key regulators of TGF-b/bone morphogenetic protein (BMP) signaling by negative feedback loops. They can form stable complexes with activated type I receptors and thereby blocking the phosphorylation of R-Smads, or recruit ubiquitin E3 ligases, such as Smurf1/2, resulting in the ubiquitination and degradation of the activated type I receptors. Besides, these inhibitory Smad proteins also inhibit TGF-b/BMP signaling in the nucleus by interacting with transcriptional repressors, such as histone deacetylases, Hoxc-8, and CtBP, or disrupting the formation of the TGF-b-induced functional Smad-DNA complexes. Smad7 is in turn regulated by different stimuli, including TGF-b ,I FN-g, TNF-a as well as ultraviolet and TPA, and mediates the crosstalk between TGF-b and other signaling pathways. Deregulation of Smad7 expression has been associated with various human diseases, such as tissue fibrosis, inflammatory disease as well as carcinogenesis. Overexpression of Smad7 has been shown to antagonize TGF-b-mediated fibrosis, carcinogenesis, and inflammation, suggesting a therapeutic potential of Smad7 to treat these diseases.

/pdf/regulation-of-tgf-b-signaling-by-smad7-z18ws3tu6z.pdf

Regulation of TGF-β signaling by Smad7

Fibrodysplasia ossificans progressiva (FOP), a rare and disabling genetic condition of congenital skeletal malformations and progressive heterotopic ossification (HO), is the most catastrophic disorder of HO in humans. Episodic disease flare-ups are precipitated by soft tissue injury, and immobility is cumulative. Recently, a recurrent mutation in activin receptor IA/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor, was reported in all sporadic and familial cases of classic FOP, making this one of the most highly specific disease-causing mutations in the human genome. The discovery of the FOP gene establishes a critical milestone in understanding FOP, reveals a highly conserved target for drug development in the transforming growth factor (TGF)-β/BMP signalling pathway, and compels therapeutic approaches for the development of small molecule signal transduction inhibitors for ACVR1/ALK2. Present management involves early diagnosis, assiduous avoidance of iatrogenic harm, and symptomatic amelioration of painful flare-ups. Effective therapies for FOP, and possibly for other common conditions of HO, may potentially be based on future interventions that block ACVR1/ALK2 signalling.

Fibrodysplasia ossificans progressiva

Immunophilins consist of a family of highly conserved proteins binding with immunosuppressive drugs such as FK506, rapamycin and cyclosporin A. FK506-binding protein (FKBP) is one of two major immunop

/pdf/fkbp-family-proteins-immunophilins-with-versatile-biological-2caiie3dho.pdf

FKBP Family Proteins: Immunophilins with Versatile Biological Functions

Accumulating evidence suggests that E3 ubiquitin ligases play important roles in cancer development In this article, we provide a comprehensive summary of the roles of the Nedd4-like family of E3 ubiquitin ligases in human cancer There are nine members of the Nedd4-like E3 family, all of which share a similar structure, including a C2 domain at the N-terminus, two to four WW domains in the middle of the protein, and a homologous to E6-AP COOH terminus domain at the C-terminus The assertion that Nedd4-like E3s play a role in cancer is supported by the overexpression of Smurf2 in esophageal squamous cell carcinoma, WWP1 in prostate and breast cancer, Nedd4 in prostate and bladder cancer, and Smurf1 in pancreatic cancer Because Nedd4-like E3s regulate ubiquitin-mediated trafficking, lysosomal or proteasomal degradation, and nuclear translocation of multiple proteins, they modulate important signaling pathways involved in tumorigenesis like TGFβ, EGF, IGF, VEGF, SDF-1, and TNFα Additionally, several Nedd4-like E3s directly regulate various cancer-related transcription factors from the Smad, p53, KLF, RUNX, and Jun families Interestingly, multiple Nedd4-like E3s show ligase independent function Furthermore, Nedd4-like E3s themselves are frequently regulated by phosphorylation, ubiquitination, translocation, and transcription in cancer cells Because the regulation and biological output of these E3s is such a complex process, study of the role of these E3s in cancer development poses some challenges However, understanding the oncogenic potential of these E3s may facilitate the identification and development of biomarkers and drug targets in human cancer

The Nedd4-like family of E3 ubiquitin ligases and cancer.

The cytoplasmic immunophilin FKBP12, a 12 kDa FK506-binding protein, has been shown to act as an inhibitor for transforming growth factor-beta (TGF-beta) signaling. FKBP12 binds to the glycine- and serine-rich motif (GS motif) of the TGF-beta type I receptor, and functions as a secure switch to prevent the leaky signal. Upon stimulation with ligand, FKBP12 is released from the receptor to fully propagate the signal. We found that activin, a member of TGF-beta superfamily, also induced the dissociation of FKBP12 from the activin type I receptor (ALK4). However, we observed that the released FKBP12 associates again with the receptor a few hours later. FKBP12 also interacted with another inhibitory molecule of activin signal, Smad7, in an activin-dependent manner, and formed a complex with Smad7 on the type I receptor. FK506, a chemical ligand for FKBP12, which dissociates FKBP12 from the receptor, decreased the interaction between Smad7 and Smad ubiquitin regulatory factor 1 (Smurf1). FK506 also inhibited the ubiquitination of the type I receptor by Smurf1. These findings indicate a new inhibitory function of FKBP12 as an adaptor molecule for the Smad7-Smurf1 complex to regulate the duration of the activin signal.

/pdf/fkbp12-functions-as-an-adaptor-of-the-smad7-smurf1-complex-43ohbo9flp.pdf

FKBP12 functions as an adaptor of the Smad7-Smurf1 complex on activin type I receptor.

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FKBP12 functions as an adaptor of the Smad7-Smurf1 complex on activin type I receptor.