The Hippo tumor suppressor pathway functions to limit tissue growth and organ size by inhibiting proliferation and inducing apoptosis. Dysregulation of the Hippo pathway contributes to tumorigenesis. The key downstream effectors of the Hippo pathway are the transcription co-activator YAP, which is phosphorylated and inhibited by the Hippo pathway kinase Lats. YAP overexpression and hyperactivation are found in human cancers. Extensive studies have identified many intracellular proteins that modulate the Hippo pathway. However, key questions regarding the extracellular signals and cell surface receptors for the Hippo pathway have not been addressed. We recently discovered that G-protein coupled receptors (GPCR) and their cognate ligands regulate the Hippo pathway. GPCR modulates many intracellular signaling molecules including protein kinase A (PKA) and protein kinase C (PKC). PKA is activated by cAMP, a second messenger that is elevated by stimulation of Gs-coupled receptor. PKC is activated by diacylglycerol that is also a second messenger elevated by Gq/11- coupled receptors. Both PKA and PKC are involved in a wide range of cellular regulation, including gene expression and cell growth. Our preliminary studies reveal that PKA and PKC potently modulate YAP. PKA inhibits YAP by increasing phosphorylation while PKC activates YAP by inducing dephosphorylation. The long- term goal of this project is to elucidate the mechanism of YAP regulation by PKA and PKC, to understand the regulation and function of the Hippo-YAP pathway in cell growth, organ size, tumorigenesis and cancer metastasis, and to provide potential therapeutic targets for cancer treatment.
The Hippo signaling pathway plays a major role in organ size regulation and has also been implicated in human cancer. Our preliminary data indicate that YAP phosphorylation is stimulated by PKA and inhibited by PKC, therefore leading to YAP inhibition and activation, respectively. The goals of this proposal are to understand the mechanism of regulation and function of YAP in PKA and PKC signaling, and to elucidate the pathological functions of YAP in promoting tumorigenesis and cancer metastasis.
|Yu, Fa-Xing; Luo, Jing; Mo, Jung-Soon et al. (2014) Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell 25:822-30|
|Zhao, Bin; Guan, Kun-Liang (2014) Hippo pathway key to ploidy checkpoint. Cell 158:695-6|
|Mo, Jung-Soon; Park, Hyun Woo; Guan, Kun-Liang (2014) The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep 15:642-56|
|Kim, Young Chul; Park, Hyun Woo; Sciarretta, Sebastiano et al. (2014) Rag GTPases are cardioprotective by regulating lysosomal function. Nat Commun 5:4241|
|Yu, Fa-Xing; Guan, Kun-Liang (2013) The Hippo pathway: regulators and regulations. Genes Dev 27:355-71|
|Yuan, Hai-Xin; Xiong, Yue; Guan, Kun-Liang (2013) Nutrient sensing, metabolism, and cell growth control. Mol Cell 49:379-87|
|Dai, Xiaoming; She, Peilu; Chi, Fangtao et al. (2013) Phosphorylation of angiomotin by Lats1/2 kinases inhibits F-actin binding, cell migration, and angiogenesis. J Biol Chem 288:34041-51|
|Zhao, Di; Zou, Shao-Wu; Liu, Ying et al. (2013) Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is decreased in pancreatic cancer. Cancer Cell 23:464-76|
|Yu, Fa-Xing; Zhang, Yifan; Park, Hyun Woo et al. (2013) Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation. Genes Dev 27:1223-32|
|Russell, Ryan C; Tian, Ye; Yuan, Haixin et al. (2013) ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat Cell Biol 15:741-50|
Showing the most recent 10 out of 20 publications