Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation

Fa-Xing Yu; Yifan Zhang; Hyun Woo Park; Jenna L. Jewell; Qian Chen; Yaoting Deng; Duojia Pan; Susan S. Taylor; Zhi-Chun Lai; Kun-Liang Guan

doi:10.1101/gad.219402.113

Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation

¹Department of Pharmacology,
²Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA;
³Department of Biology,
⁴Department of Biochemistry and Molecular Biology, Intercollege Graduate Degree Program in Genetics, The Pennsylvania State University, University Park, Pennsylvania 16802, USA;
⁵Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
⁶Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California 92093, USA

Abstract

The Hippo tumor suppressor pathway plays an important role in tissue homeostasis that ensures development of functional organs at proper size. The YAP transcription coactivator is a major effector of the Hippo pathway and is phosphorylated and inactivated by the Hippo pathway kinases Lats1/2. It has recently been shown that YAP activity is regulated by G-protein-coupled receptor signaling. Here we demonstrate that cyclic adenosine monophosphate (cAMP), a second messenger downstream from Gα_s-coupled receptors, acts through protein kinase A (PKA) and Rho GTPases to stimulate Lats kinases and YAP phosphorylation. We also show that inactivation of YAP is crucial for PKA-induced adipogenesis. In addition, PKA activation in Drosophila inhibits the expression of Yorki (Yki, a YAP ortholog) target genes involved in cell proliferation and death. Taken together, our study demonstrates that Hippo–YAP is a key signaling branch of cAMP and PKA and reveals new insight into mechanisms of PKA in regulating a broad range of cellular functions.