UC San Diego

The recent TCGA study identified the Hippo pathway as one of the nine major signaling pathways that are frequently altered in human cancer. The Hippo pathway is a master regulator of cell proliferation, cell death, and cell differentiation. Its dysregulation has been implicated intensively in human diseases especially cancer. Exploring the regulatory network of the Hippo pathway answers basic biological questions such as how organ size is controlled during development as well as contributes to cancer target therapy. My research focuses on elucidating how Hippo pathway is regulated by cellular stress, more specifically osmotic stress. Physiological effect of the Hippo pathway is carried through transcription co-activator YAP. We found that osmotic stress induces YAP nuclear translocation even though it is phosphorylated at Ser 127 site, where its phosphorylation has been implicated to cause YAP cytoplasmic retention. We identified a novel phosphorylation site on YAP and a novel upstream regulator NLK that lead to YAP activation and subsequent cell proliferation. This finding alters the well-established dogma that YAP is inhibited by phosphorylation.

The mechanisms by which osmotic stress-activated the Hippo pathway remained unclear. We discovered that NF2 lipid binding is essential for osmotic stress-induced activation of the Hippo pathway. We showed that osmotic stress induces ARF6 and PIP5K family interaction, leading to PIP5K activation and enhanced PI(4,5)P2 membrane distribution. Membrane-associated PI(4,5)P2 interacts with NF2, which further induces downstream Hippo pathway activation. This work completes the missing piece in the field on how NF2 is involved in Hippo pathway activation. Completion of these projects not only address fundamental questions in Hippo regulation but also provide valuable leads for therapeutic intervention for cancer treatment.