The Role of TGF𝜷 Signaling in Squamous Cell Cancer: Lessons from Mouse Models

Figure 1

Schematic of TGFβ1 signaling pathway and its regulation. TGFβ1 is secreted and sequestered in the extracellular matrix as a biologically inactive complex composed of the TGFβ1 peptide linked to the latency-associated peptide (LAP) and a member of the latent TGFβ-binding protein (LTBP) family. Activation of latent TGFβ1 allows binding of active peptide dimer to TβRII and formation of a heterotetrameric receptor complex Between TβRI and TβRII. Coreceptors such as betaglycan act to enhance TGFβ binding to its receptors. TβRII, phosphorylates the cytoplasmic domain of TβRI and activates its serine-threonine kinase activity towards the R-Smads, Smad2, or Smad3, Phosphorylation of an R-Smad for allows complex formation with Smad4 and translocation to the nucleus, where binding to SBE target sites in gene promoters activates transcription with many other cofactors. Dephosphorylation of R-Smads by Smad phosphatases such as PPM1A attenuate signaling and cause Smads to recycle to the cytoplasm. Smad7 can block type I receptor phosphorylation of R-Smads and in conjunction with E3 ubiquitin ligases such as Smurf1 cause polyubiquitination and degradation of TβRI. Smurf1 and similar proteins have also been implicated in degradation of R-Smads.