The Molecular Pathogenesis and Clinical Implications of Hepatocellular Carcinoma

Figure 2

The RAF/MEK/ERK and the PI3K/AKT/mTOR signaling pathways are shown. Proangiogenic and proliferative growth factors activate the RAF/MEK/ERK pathway. The small GTPase RAS and the serine/threonine kinase RAF are the key molecular signal regulators. Intermediate signaling is regulated by MEK, which is responsible for phosphorylating and activating the final downstream signaling ERK molecules. ERK regulates cellular activity, indirect inducers of gene expression, and transcription factors in the AP-1 family such as c-JUN and c-FOS and cell cycle-related kinases. Binding of these growth factors to their receptors also activates PI3K, which subsequently produces the lipid second messenger, and in turn activates serine/threonine kinase AKT. Activated AKT also phosphorylates several cytoplasmic proteins, most notably mTOR. The activation of mTOR increases cellular proliferation, and inactivation of BAD decreases apoptosis and increases cell survival. This pathway is negatively regulated by the phosphatase and tensin homolog deleted on chromosome 10 (PTEN), which targets the lipid products of PI3K for dephosphorylation.