MEK1 promotes YAP and their interaction is critical for tumorigenesis in liver cancer

Abstract

a b s t r a c tMitogen-activated protein kinase kinase 1 (MAP2K1/MEK1) as well as Yes-associated protein (YAP), the downstream effector of Hippo signaling pathway, is linked to hepatocarcinogenesis. However, little is known about whether and how MEK1 interacts with YAP. In this study, we find that MEK1-YAP interaction is critical for liver cancer cell proliferation and maintenance of transformed phenotypes both in vitro and in vivo. Moreover, MEK1 and YAP proteins are closely correlated in human liver cancer samples. Mechanistically, inhibition of MEK1 by both PD98059 and U0126 as well as RNAi reduces beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC), which acts as a potential endogenous YAP protector. Structured summary of protein interactions:YAP physically interacts with MEK1 by anti tag coimmunoprecipitation (View interaction) BTRC and MEK1 colocalize by fluorescence microscopy (View interaction) YAP physically interacts with MEK1 by anti bait coimmunoprecipitation (View interaction) MEK1 physically interacts with BTRC by anti tag coimmunoprecipitation (View interaction) BTRC physically interacts with MEK1 by anti bait coimmunoprecipitation (View interaction) MEK1 and YAP colocalize by fluorescence microscopy (View interaction)

MiR-506 suppresses proliferation of hepatoma cells through targeting YAP mRNA 3′UTR

“…Identifying the underlying mechanisms of YAP regulation will help facilitate the study of YAP as a novel target for the treatment of cancer. It has been reported that mitogen-activated protein kinase kinase 1 (MEK1) promotes YAP expression and that their interaction is critical for tumorigenesis in liver cancer [30] . In addition, there is a novel positive auto-regulatory feedback loop that underlies the interaction between YAP and c-Myc in liver cancer, which suggests that YAP and c-Myc link the Hippo-YAP and c-Myc pathways [13] .…”

CD166 positively regulates MCAM via inhibition to ubiquitin E3 ligases Smurf1 and βTrCP through PI3K/AKT and c-Raf/MEK/ERK signaling in Bel-7402 hepatocellular carcinoma cells

“…In our previous study [2], we reported CD166 is involved in the regulation of YAP, a central oncogenic protein during liver tumorigenesis [2,10,11,[17][18][19][20]. Interestingly, the function of YAP is enhanced by TRIB2, which is an ubiquitin E3 ligase adaptor protein that interacts with E3 ligases, βTrCP, COP1 and Smurf1 [12,13,20,21].…”

“…Cell proliferation, Caspase3/7 activity, Immunoprecipitation (IP), softagar assays and xenograft mouse experiments Cell proliferation was measured by an MTT-based proliferation assay, as described previously [10][11][12]. The caspase-3/7 activity was determined using the Caspase-Glo 3/7 assay system (Promega, Madison, WI).…”

“…The caspase-3/7 activity was determined using the Caspase-Glo 3/7 assay system (Promega, Madison, WI). The conventional IPs were performed as previously described [10][11][12][13]. The denaturation IPs for detection of ubiquitination were performed according to the study by Fang, et al [14] with slight modifications, briefly, lysates from Bel-7402 cells under different treatment were prepared in Western/IP lysis buffer (Beyotime, Haimen, China).…”

The Hippo signaling pathway in liver regeneration and tumorigenesis

“…Other than MAPK14/P38, MEK/ERK proteins belong to the mitogenic signaling cascade and are linked to hepatocarcinogenesis as well. Sun's group further demonstrated that MEK1 promotes YAP protein expression through BTRC, and MEK1 and YAP are closely correlated in liver cancer samples, suggesting the important role of their interaction in liver tumorigenesis [42].…”