Linker phosphorylation of Smad3 promotes fibro-carcinogenesis in chronic viral hepatitis of hepatocellular carcinoma

Figure 1 Reversibility of phospho-Smad3 signaling between tumor suppression and fibro-carcinogenesis. A: Additional treatment of transforming growth factor-β (TGF-β) activates TGF-β receptor type I (TβRI), further leading to direct phosphorylation of Smad3C, which inhibits normally hepatocytic growth by upregulating p21^WAF1 transcription; B: Mitogens drastically alter phospho-Smad3 signaling via the c-Jun N-terminal kinase (JNK) pathway, increasing nuclear fibro-carcinogenic pSmad3L activity while shutting down TGF-β-dependent cytostatic pSmad3C. Although the TGF-β signal weakly phosphorylates Smad3L in normal hepatocytes (dotted line), hepatitis viral components, including HBx, pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), and somatic mutations such as Ras, additively transmit a fibro-carcinogenic signal through the JNK-dependent pSmad3L pathway to participate in hepatocytic growth and ECM deposition, possibly by stimulating transcription of c-Myc and PAI-1 genes. Linker phosphorylation of Smad3 indirectly prevents COOH-tail phosphorylation, pSmad3C-mediated p21^WAF1 transcription and cytostatic function; C: Either various JNK inhibitors or a Smad3 mutation causing lack of JNK phosphorylation sites in the linker region can eliminate fibro-carcinogenic pSmad3L signaling, restoring or maintaining the tumor-suppressive pSmad3C signaling characteristic of mature hepatocytes.