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.
Lu
Chengrong
C
Department of Genomics and Proteomics, Beijing Institute of Radiation Medicine, Chinese National Human Genome Center at Beijing, Beijing 100850, P. R. China.
Li
Yong
Y
Zhao
Yanlin
Y
Xing
Guichin
G
Tang
Fei
F
Wang
Qingming
Q
Sun
Yuhui
Y
Wei
Handong
H
Yang
Xiaoming
X
Wu
Chutse
C
Chen
Jianguo
J
Guan
Kun-Liang
KL
Zhang
Chenggang
C
Chen
Huipeng
H
He
Fuchu
F
D000818:Animals; D000075686:COP9 Signalosome Complex; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D010447:Peptide Hydrolases; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000502:physiology*; D020798:Two-Hybrid System Techniques
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D017228:Hepatocyte Growth Factor; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex