Intracrine hepatopoietin potentiates AP-1 activity through JAB1 independent of MAPK pathway

Many growth factors and cytokines are involved in liver regeneration. Of them, only hepatopoietin (HPO)/ALR (augmenter of liver regeneration) is a specifically hepatotrophic factor originally identified from the cytosol of regenerating or hyperplastic hepatic cells. Previous reports indicate that extracellular HPO triggers the MAPK pathway by binding its specific receptor on the cell surface. However, its function in the cytosol of hepatocytes is unclear. Here we identified that JAB1 (Jun activation domain-binding protein 1), a co-activator of AP-1, which is essential for liver regeneration, specifically interacts with intracellular HPO. JAB1 colocalizes with HPO in nuclei of hepatic cells or COS-7 cells. As an intracrine factor, the intracellular function of HPO is to increase c-Jun phosphorylation independent of c-Jun amino-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) -1 and -2, and leads to potentiation of JAB1-mediated AP-1 activation. Amino acids 1-63 of HPO molecule are sufficient to bind to JAB1, but the full-length HPO is necessary for its intracellular signaling. Taken together, these results elucidate a novel mechanism of intracrine cytokine signaling by specifically modulating the AP-1 pathway through JAB1, in a MAPK-independent fashion.