Crosstalk of LKB1- and PTEN-regulated signals in liver morphogenesis and tumor development.

Unlabelled: Liver kinase B 1 (LKB1 or STK11) and PTEN (phosphatase and tensin homologue deleted on chromosome 10) are two tumor suppressors that regulate the mTOR signaling pathway. Deletion studies show that loss of either ( ) or ( ) leads to liver injury and development of hepatocarcinoma. In this study, we investigated the crosstalk of LKB1 and PTEN loss during tumorigenesis and liver development. We show here that haplo-insufficiency of in the liver leads to advanced tumor development in the null mice ( ). Our analysis shows that LKB1 and PTEN interacted with each other in their regulation of fatty acid synthase as well as p21 expression. The combined loss of LKB1 and PTEN ( ) also led to the inability to form zonal structures in the liver. The lack of metabolic zonal structures is consistent with the inability of the livers to store glycogen as well as elevated plasma bilirubin and alanine aminotransferase (ALT), indicative of liver dysfunction. These structural and functional defects are associated with cytoplasm distribution of a canalicular membrane protein MRP2 (multidrug resistant protein 2) which is responsible for clearing bilirubin. This observed regulation of MRP2 by LKB1 likely contributed to the lack of cellular polarity and the early lethality phenotype associated with homozygous loss of alone or in combination with . Finally, deletion does not rescue the precocious ductal plate formation reported for deleted livers.

Conclusion: Our study dissected the functional and molecular crosstalk of PTEN and LKB1 and elucidate key molecular targets for such interaction.