Dual Role of a C-Terminally Truncated Isoform of Large Tumor Suppressor Kinase 1 in the Regulation of Hippo Signaling and Tissue Growth

摘要

The considerable amount of experimental evidence has defined the Hippo pathway as a tumor suppressive pathway and increased expression and/or activity of its oncogenic effectors is frequently observed in cancer. However, clinical studies have failed to attribute cancer development and progression to mutations in the pathway. In explaining this conundrum, we investigated the expression and functions of a C-terminally truncated isoform of large tumor suppressor kinase 1 (LATS1) called short LATS1 (sLATS1) in human cell lines and i>Drosophila . Intriguingly, through overexpression of sLATS1, we demonstrated that sLATS1 either activates or suppresses the activity of Yes-associated protein (YAP), one of the effectors of the Hippo pathway, in a cell type-specific manner. The activation is mediated through inhibition of full-length LATS1, whereas suppression of YAP is accomplished through sLATS1–YAP interaction. In HEK293T cells, the former mechanism may affect the cellular response more dominantly, whereas in U2OS cells and developing tissues in i>Drosophila , the latter mechanism may be solely carried out. Finally, to find the clinical relevance of this molecule, we examined the expression of i>sLATS1 in breast cancer patients. The transcriptome analysis showed that the ratio of i>sLATS1 to i>LATS1 was increased in tumor tissues comparing to their adjacent normal tissues.