Extracellular signal-regulated kinase (ERK) is normally an integral part of the mitogen-activated protein kinase (MAPK) signaling pathway that allows the transduction of varied cellular alerts to last effectors and regulation of primary cellular processes. cancers cells through inhibition from the TEAD transcription activity and appearance TKI-258 inhibitor of GLUT (blood sugar transporter) [76,78,79]. MST kinase induces apoptosis through manifestation of pro-apoptotic protein NOXA in several tumor cells through phosphorylation and activation of FOXO (forkhead package O) transcription factors [80,81,82]. MST kinase directly phosphorylates and activates pro-apoptotic protein BIM, caspase-3, -9 and apoptosis in pancreatic beta-cells [83]. Hippo/MST signaling also inhibits manifestation and F2rl3 activity of several anti-apoptotic proteins such as IAP, MCL1 and BCL-XL [84,85,86]. MST also activates caspases and caspases potentiate MST kinase activity in positive opinions loops. MST signaling was described as a potent activator of caspase-3, -7,-9 and an intrinsic apoptotic pathway through mechanisms discussed above and cleavage of the MST kinase by caspase-3, -7 potentiates its pro-apoptotic activity [87,88,89]. Moreover, activation of caspase-8 from the Hippo/MST signaling was also recorded [47,90]. Interplay between caspase-8 and ERK signaling represents one of the important mechanisms in the EGFR signaling pathway as demonstrated by several reports rendering MST as a regulator of this process [55,62,63]. Finally, a computational model predicting diverse dynamic profiles of the Hippo-ERK interaction network was constructed [91]. 8. Activation of the Hippo/MST Signaling Pathway in Cancer Cells Hippo/MST signaling and ERK signaling pathways share TKI-258 inhibitor several targets to regulate proliferation and cell death in cancer cells (Figure 3). Activation of the Hippo/MST signaling was demonstrated as a crucial mechanism responsible for activity of several anti-cancer compounds. All these results suggest the synergistic effect between inhibitors/activators of ERK signaling and activators of the Hippo/MST signaling for cancer therapy. AKT kinase phosphorylates MST1 at T120 and inhibits MST1 activity [92]. Targeted inhibition of the PI3K/AKT/mTOR signaling axis triggers activation of the MST kinase and inhibits activity of YAP effector in a broad spectrum of cancer cells. Treatment of T-ALL cells with PI3K inhibitor GDC0941 activates MST1 kinase, ERK kinase and apoptosis [47]. LY294002 inhibitor induces suppression of cell growth and apoptosis in castration-resistant C4-2 prostate cancer cells and HCT116 colon cancer cells [92,93]. Wortmannin blocks YAP activation and MYC expression mediated by EGF in hepatocellular carcinoma and mammary epithelial cells [94,95]. The combination of PI3K/mTOR inhibitors with FGFR4 inhibitor BLU9931 potentiates MST1 activation and induces apoptosis in HER2+ breast cancer cells [96]. Pan-MTOR inhibitor MLN0128 activates caspase-3, -7 and promotes apoptosis in intrahepatic cholangiocarcinoma induced in mice by YAP over-expression [97]. Rapamycin-derived compound temsirolimus triggers YAP protein degradation by autophagy in human angiomyolipoma [98]. Several natural compounds with anti-cancer activity were described as potent activators of MST kinase in cancer cells. Naphthoquinonic compound shikonin disturbs YAP1-TEAD1 interaction through the activation of MST1 and ERK signaling in T-ALL cells [76,99]. Flavonol fisetin activates LATS and ERK kinase and induces apoptosis in osteosarcoma cells [100]. The polyphenolic compound curcumin induces cell cycle arrest, autophagy and apoptosis through the production of reactive oxygen species (ROS), activation TKI-258 inhibitor of ERK kinase, MST kinase, caspase-3, -9 and down-regulation of YAP protein in various cancer cell models [101,102,103]. The inhibition of oncogenic Hippo-YAP signaling through the activation of LKB1 tumor suppressor by honokiol abrogates breast tumorigenesis and metastasis in mice [104,105]. Several other drugs and compounds were described as activators of the Hippo/MST signaling in cancer cells. Supplement E analogues activate MST1 and TKI-258 inhibitor ERK signaling in T-ALL cells and breasts cancer cells leading to apoptosis induction [8,80]. An inhibitor of HMGCR, the rate limiting enzyme of the mevalonate biosynthesis, suppresses malignant mesothelioma cells through blocking of the YAP/CD44 axis [106]. Pyranocoumarin decursin stimulates LATS kinase phosphorylation and YAP protein degradation through activation of TRCP ubiquitin E3 ligase in hepatocellular carcinoma [107]. Tetracyclic triterpene cucurbitacin B induces apoptosis through activation of LATS kinase and caspase-3 in colorectal carcinoma cells [108]. Flavone apigenin disrupts YAP-TEAD interaction and decreases viability and migration of triple-negative breast cancer cells as well as tumor formation in vivo [109]. Open in a separate window Figure 3 Cross-talk of the mitogen-activated protein kinase (MAPK)/ERK signaling pathway and mechanism of cell death induction through the ERK-Hippo interplay. 9. Combination Targeting of MAPK/ERK, PI3K/AKT/MTOR and Hippo/MST Pathways in Cancers Targeted inhibition of the.