TGF-ß Receptor Kinase Inhibitors

Transforming growth factor-ß (TGF-ß), a member of the TGF superfamily of proteins that includes activins, inhibins, and bone morphogenetic proteins (BMPs), regulates a wide array of cellular processes including cell differentiation, cellular senescence, immune response, wound healing, and apoptosis. TGF-ß signaling promotes growth and development during early embryogenesis. However, in mature tissues many cells respond to TGF-ß with either a cytostatic or apoptotic response. TGF-ß signaling involves its binding to the TGF-ß receptor type II (TGF-ßRII), which allows it to recruit TGF-ß receptor type I (TGF-ß RI) and assemble it as a heterodimeric receptor complex. TGF-ßRII phosphorylates TGF-ßRI in the glycine-serine rich region (GS sequence) and activates the serine/threonine kinase activity of TGFßRI, which in turn phosphorylates receptor-linked Smad (Small mothers against decapentaplegic) proteins. To prevent any spontaneous phosphorylation of Smads, the inhibitor molecule FKBP12 binds to the GS region of the TGF-ßRI and blocks the access of TGF-ßRII to this domain. This inhibitory effect is removed upon TGF-ß binding to the receptor. The TGF-ß receptor complex is internalized by lipid-raft and clathrin endocytotic pathways. The clathrin endocytotic pathway is considered to be essential for activation of the TGF-ß signaling cascade. The lipid-raft pathway for TGF-ß receptor internalization negatively regulates TGF-ß signaling by inducing receptor complex degradation.

The activated TGF-ßRI in the internalized complex phosphorylates specific Smad proteins. At least nine different Smad proteins have been reported in vertebrates that are classified as: (a) receptor-activated Smads (R-Smads): Smad1, Smad2, Smad3, Smad5, and Smad8; (b) co-mediator Smads: Smad4 and Smad10; and (c) inhibitory Smads (I-Smads): Smad6 and Smad7. R-Smads2 and 3 are involved in TGF-ß and activin signaling, whereas R-Smads 1, 5, and 8 are mediators of BMP signaling. Smad2 and Smad3 are directly phosphorylated by TGF-ßRI, which changes their conformation and releases these R-Smads from the receptor complex. The C-terminal phosphoserines of R-Smads are recognized by the Mad Homology 2 (MH2) domain of Smad4 that enables them to form a heterodimeric complex (R-Smad/Co-Smad). This complex then translocates to the nucleus where Smad proteins bind to their cognate DNA binding sites with low affinity. This binding is further enhanced in the presence of transcriptional co-activators. Both Smad3 and Smad4 bind to DNA sequences known as the Smad-binding elements (SBE); however, Smad2 participates in DNA-bound complexes via its interaction with Smad4. Genes for cyclin-dependent kinase inhibitors, p21 and p15, which mediate growth inhibitory processes, are up-regulated by TGF-ß stimulation. TGF-ß-induced growth inhibition is also achieved by down-regulation of c-Myc, which further amplifies the expression of p21 and p15.

Apart from its role as a growth inhibitor and tumor suppressor, TGF-ß also promotes tumor metastasis during late stages of tumor development. TGF-ß also modulates cell invasion, immune regulation, and microenvironment modification that cancer cells exploit to their advantage. Dysregulated TGF-ß signaling has been implicated in the pathogenesis of human solid tumors. Any disruption in TGF-ß signaling, either by mutational inactivation or by down regulation of expression of any of the signaling components involved, can lead to tumor development.

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