TGFβ signaling in normal colonic epithelium and cancer cells. Panel A describes the functional pathway of TGFβ signaling in normal colonic epithelial cells. TGFβ ligand binding with TGFβRII recruits TGFβRI into a tetrameric receptor complex resulting in transphosphorylation and activation of TGFβRI. After phosphorylation, the TGFβRI becomes an active kinase which phosphorylates Smad 2 and Smad3. SARA (Smad Anchor for Receptor Activation), a scaffolding protein facilitates interaction between Smad2, Smad3 and TGFβRI. Phosphorylated Smad2 and Smad3 allow the formation of homo- and heterodimerization complex, including Smad4. The Smad complex then translocates into nucleus, binds with DNA, and stimulates the expression of target genes including p15 (inhibitor of cell cycle kinase that controls cell cycle into G1 phase) and PAI-1 (inhibitor of protease 1 that degrades extracellular matrix proteins during metastasis). Panel B shows the abnormal pathway of TGFβ signaling in colon cancer cells. Many colon cancer cells with microsatellite instability (MSI) due to defective mismatch repair (MMR) activity induce mutations in TGFβRII gene. Often, these are frameshift mutations that insert or delete one or two adenine bases located within a 10 base-pair polyadenine repeat region (base-pairs 709–718, codons 125–128; referred to as BAT-RII) of TGFβRII gene. These mutations encode TGFβRII proteins truncated between 129 and 161 amino acids of the cytoplasmic domain which causes functional inactivation of these proteins. Thus, the loss of TGFβ signaling may abolish cell cycle control and induce metastasis of colon cancer cells by inhibiting p15 and PAI-1 genes expression, respectively.