Genes & Development



SUPPLEMENTAL MATERIALA YAP/TAZ-induced feedback mechanism regulatesHippo pathway homeostasisToshiro Moroishi,1 Hyun Woo Park,1 Baodong Qin,1,2 Qian Chen,3 Zhipeng Meng,1 Steven W. Plouffe,1 Koji Taniguchi,4 Fa-Xing Yu,5 Michael Karin,4 Duojia Pan,3 and Kun-Liang Guan1,*1Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA2Department of Laboratory Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.3Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA4Departments of Pharmacology and Pathology, University of California, San Diego, La Jolla, California 92093, USA5Children's Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China*Correspondence: kuguan@ucsd.eduFigures S1 to S7Supplemental figure legendsSupplemental experimental proceduresSUPPLEMENTAL FIGURE LEGENDSFigure S1. Rescue experiments and knockdown efficiency for shRNA studies, effects of YAP/TAZ on each other's mRNA levels, related to Figure 1(A) YAP re-expression abolishes TAZ accumulation in YAP knockdown MCF10A cells. MCF10A cells stably expressing shRNAs specific for YAP were infected with retroviruses encoding Myc-YAP. Immunoblot analysis (IB) was performed with the indicated antibodies.(B) Knockdown efficiency of TEAD1/3/4 shRNA. Total RNA extracted from MCF10A cells infected with lentiviral vectors encoding shRNAs specific for TEAD1/3/4 (or control) was subjected to RT and real-time PCR analysis of the indicated mRNA. Data are means ± SD of triplicates from a representative experiment.(C) TEAD1 re-expression stimulates YAP-induced TAZ reduction in TEAD1/3/4 knockdown MCF10A cells. MCF10A cells stably expressing Myc-YAP(5SA) and shRNAs specific for TEAD1/3/4 were infected with retroviruses encoding Myc-TEAD1. Immunoblot analysis was performed with the indicated antibodies.(D) Overexpression of YAP has little effect on the mRNA abundance of TAZ. Total RNA extracted from MCF10A cells stably expressing Myc-YAP(5SA), Myc-YAP(5SA/S94A), or control vector was subjected to RT and real-time PCR analysis of WWTR1 mRNA. Data are means ± SD of triplicates from a representative experiment.(E) Overexpression of TAZ has little effect on the mRNA abundance of YAP. Total RNA extracted from MCF10A cells stably expressing FLAG-TAZ(4SA), FLAG-TAZ(4SA/S51A), or control vector was subjected to RT and real-time PCR analysis of YAP1 mRNA. Data are means ± SD of triplicates from a representative experiment.Figure S2. Effect of YAP/TAZ on mRNA level of MYC or AMOT, related to Figure 2(A) Overexpression of YAP/TAZ does not increase the mRNA abundance of MYC. Total RNA extracted from MCF10A cells stably expressing Myc-YAP(5SA), Myc-YAP(5SA/S94A), FLAG-TAZ(4SA), FLAG-TAZ(4SA/S51A), or control vector was subjected to RT and real-time PCR analysis of MYC mRNA. Data are means ± SD of triplicates from a representative experiment.(B) Overexpression of TAZ has little effect on the mRNA abundance of AMOT. Total RNA extracted from MCF10A cells stably expressing FLAG-TAZ(4SA), FLAG-TAZ(4SA/S51A), or control vector was subjected to RT and real-time PCR analysis of AMOT mRNA. Data are means ± SD of triplicates from a representative experiment.Figure S3. TAZ induces LATS2 expression, knockdown efficiency of YAP shRNA, related to Figure 3(A) TAZ induces the transcription of LATS2, but not that of LATS1. Total RNA extracted from MCF10A cells stably expressing FLAG-TAZ(4SA), FLAG-TAZ(4SA/S51A), or control vector was subjected to RT and real-time PCR analysis of the indicated mRNA. Data are means ± SD of triplicates from a representative experiment.(B) Knockdown efficiency of YAP shRNA. Total RNA extracted from MCF10A cells infected with lentiviral vectors encoding shRNAs specific for YAP (or control) was subjected to RT and real-time PCR analysis of YAP1 mRNA. Data are means ± SD of triplicates from a representative experiment.Figure S4. YAP and TAZ stimulate the intrinsic kinase activity of LATS1/2 through NF2 induction, related to Figure 4(A) MST1/2 re-expression prevents YAP dephosphorylation in MST1/2 deficient HEK293A cells. Wild-type (WT) and MST1/2 double knockout (DKO) HEK293A cells transfected (or not) with expression vectors for the indicated protein were subjected to immunoblot (IB) analysis. Where indicated, gels containing phos-tag were employed for assessment of YAP phosphorylation status (top).(B) TAZ activates LATS. HEK293A cells stably expressing FLAG-TAZ(4SA), FLAG-TAZ(4SA/S51A), or control vector were subjected to immunoblot analysis. HM, hydrophobic motif.(C) MST1/2 are largely required for YAP-induced activating phosphorylation of LATS1/2. WT and MST1/2 DKO HEK293A cells infected with retroviruses encoding Myc-YAP(5SA) (or control empty retrovirus) were subjected to immunoblot analysis.(D) YAP and TAZ induce the transcription of NF2. Total RNA extracted from MCF10A cells stably expressing the indicated constructs were subjected to RT and real-time PCR analysis of NF2 mRNA. Data are means ± SD of triplicates from a representative experiment.(E) Both endogenous YAP and TEAD1 bind to the NF2 promoter. MCF10A cells starved in serum-free medium for 18 h were stimulated with 5% horse serum for 2 h. The cells were then subjected to chromatin immunoprecipitation (ChIP) with antibodies to endogenous YAP or TEAD1 (or control IgG), and the precipitated DNA was quantitated by real-time PCR analysis with primers specific for a promoter region or a control region (CR) of the indicated genes. Data are means ± SD of triplicates from a representative experiment.(F) NF2 re-expression prevents YAP dephosphorylation in NF2 deficient HEK293A cells. Wild-type (WT) and NF2 knockout (KO) HEK293A cells transfected (or not) with expression vectors for the indicated protein were subjected to immunoblot analysis. Where indicated, gels containing phos-tag were employed for assessment of YAP phosphorylation status (top).(G) NF2 is required for YAP-induced LATS activation. WT and NF2 KO HEK293A cells infected with retroviruses encoding Myc-YAP(5SA) (or control empty retrovirus) were subjected to immunoblot analysis.(H) NF2 is required for TAZ-induced activating phosphorylations of LATS1/2, but not for induction of LATS2. WT and NF2 KO HEK293A cells were infected with retroviruses encoding FLAG-TAZ(4SA), or with the empty retrovirus. Cell lysates were immunoblotted with the indicated antibodies.(I) LATS2 induction by YAP(5SA) is still operational under NF2 and MST1/2 overexpression. Tetracycline repressor-expressing HEK293A cells were infected with retroviruses encoding Myc-YAP(5SA) (or with the control empty retrovirus), transfected (or not) with expression vectors for the indicated protein, and then incubated with doxycycline (200 ng/ml) for 28 h. Immunoblot analysis was performed with the indicated antibodies.Figure S5. LATS1/2 mediate negative feedback regulation of YAP, TAZ, and AMOT, related to Figure 5(A) LATS1/2 are required for YAP-induced TAZ reduction in MCF10A cells. MCF10A cells stably expressing Myc-YAP(5SA) (or control vector) were transfected with non-targeting siRNA (control), or siRNA targeting LATS1 or LATS2. Cell lysates were collected for immunoblot (IB) analysis.(B) YAP induces the transcription of Lats2. Wild-type (WT) or Lats1–/–Lats2Δ/Δ (LATS1/2 DKO) MEFs infected with retroviruses encoding Myc-YAP(5SA) (or with the empty retrovirus) were subjected to RT and real-time PCR analysis of Lats2 mRNA. Data are means ± SD of triplicates from a representative experiment.(C) LATS1/2 are required for YAP-induced phosphorylation and accumulation of AMOT. MEFs infected as in (A) were subjected to immunoblot analysis with antibodies to the indicated proteins.Figure S6. TEADs are required for lysophosphatidic acid (LPA)-induced CTGF and CYR61 transcription, related to Figure 6(A) LPA induces YAP/TAZ target gene expression in a TEAD-dependent manner. MCF10A cells stably expressing shRNA specific for TEAD1/3/4 (or control) were starved in serum-free medium for 15 h and then stimulated with 5 μM LPA for 2 h. Total RNA were subjected to RT and real-time PCR analysis of the indicated mRNA. Data are means ± SD of triplicates from a representative experiment. Figure S7. Rescue experiment for LATS1/2 double knockout HEK293A cells, related to Figure 7(A) LATS1/2 re-expression prevents YAP dephosphorylation in LATS1/2 deficient HEK293A cells. Wild-type (WT) and LATS1/2 double knockout (DKO) HEK293A cells transfected (or not) with expression vectors for the indicated protein were subjected to immunoblot (IB) analysis. Where indicated, gels containing phos-tag were employed for assessment of YAP phosphorylation status (top).SUPPLEMENTAL EXPERIMENTAL PROCEDURESCell culture and transfectionAll cell lines were cultured under an atmosphere of 5% CO2 at 37°C. MCF10A cells were cultured in DMEM/F12 (Invitrogen) supplemented with 5% horse serum (Invitrogen), epidermal growth factor (EGF; 20 ng/ml), hydrocortisone (500 ng/ml), insulin (10 μg/ml), cholera toxin (100 ng/ml), penicillin (100 U/ml), and streptomycin (100 mg/ml). All other cells were cultured in DMEM (Invitrogen) supplemented with 10% FBS (Thermo scientific), penicillin (100 U/ml), and streptomycin (100 mg/ml). For serum starvation, cells were incubated in DMEM or DMEM/F12 without other supplements. Transfection of plasmid DNA was performed with the PolyJet DNA In Vitro Tranfection Reagent (Signagen Laboratories) according to manufacturer’s instructions. Cloning and construction of the expression plasmids were described previously PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFvPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (Zhao et al. 2007; Zhao et al. 2008). The empty pcDNA3 plasmid was included to ensure that cells were transfected with equal amounts of total DNA. Small interfering RNA (siRNA) was delivered into cells using Lipofectamine RNAiMAX (Invitrogen) according to manufacturer’s instructions.Retroviral infection and tetracycline-inducible expression systemCells stably expressing empty vector, Myc-YAP, Myc-YAP(5SA), Myc-YAP(5SA/S94A), FLAG-TAZ(4SA), FLAG-TAZ(4SA/S51A), or Myc-TEAD1 were generated by retroviral infection. 293 phoenix retrovirus packaging cells were transfected with empty vector, pQCXIH Myc-YAP, pQCXIH Myc-YAP(5SA), pQCXIH Myc-YAP(5SA/S94A), pBABE FLAG-TAZ(4SA), pBABE FLAG-TAZ(4SA/S51A), or pQCXIH Myc-TEAD1 constructs. Forty-eight hours after transfection, retroviral supernatant was supplemented with 5 μg/ml polybrene, filtered through a 0.45 μm filter, and used to infect the indicated cells. Forty-eight hours after infection, cells were selected with either 200 μg/ml hygromycin (for pQCXIH constructs) or 4 μg/ml puromycin (for pBABE constructs) in culture medium.For tetracycline-inducible expression system, MCF10A and HEK293A cells were infected with a retrovirus encoding tetracycline repressor (TetR) (pRetroX-Tet-On; Invitrogen) for 2 days. The cells were then incubated with G418 (300 μg/ml) for selection and amplification of neomycin-resistant cells. The TetR-expressing cells were then infected with retroviruses encoding YAP(S127A) or Myc-YAP(5SA) (or pRetroX-Tight-Pur empty vector for control). Forty-eight hours after infection, the cells were selected with G418 (300 μg/ml) and puromycin (4 μg/ml) in culture medium. For induction of YAP expression, the cells were incubated with doxycycline for the indicated times.Lentiviral Infection and RNA Interference (RNAi)Gene silencing by RNAi was performed with either the lentivirus-based shRNA expression or siRNA transfection. For lentiviral infection, the infection process was similar to that of retroviral infection except that the lentiviral packaging plasmids psPAX2 and pMD2.G were cotransfected into HEK293T cells for virus production. The shRNA-encoding DNA oligonucleotide inserts were generated with the use of pLKO.1 vector. The target sequences for YAP and TEAD1/3/4 were described previously PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFvPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (Zhao et al. 2008). An shRNA specific for LacZ (5'-AAGGCCAGACGCGAATTAT-3'), which did not match any existing sequence in the human database, was used as a control. For siRNA experiments, ON-TARGETplus SMARTpool siRNA (GE Dharmacon) for LATS1 (L-004632-00), LATS2 (L-003865-00), or non-targeting control (D-001810-10) were used.Gene deletion of HEK293A cells by CRISPR/Cas9 systemLATS1/2-, MST1/2-, or NF2-deficient HEK293A cells were created through the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 system PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYW48L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (Ran et al. 2013). HEK293A cells were transfected with a Cas9 expression plasmid together with single-guide RNA (sgRNA) expression plasmids (PX459; Addgene plasmid #48139). The guide sequences were designed using the CRISPR design tool at or were taken from archived guide sequences from the Genome-scale CRISPR knock-out (GeCKO2) library PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW5qYW5hPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48

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ADDIN EN.CITE.DATA (Sanjana et al. 2014). The guide sequences used are 5'-CGTGCAGCTCTCCGCTCTAA-3' for human LATS1; 5'-TACGCTGGCACCGTAGCCCT-3' for human LATS2; 5'-ATACACCGAGATATCAAGGC-3' for human MST1; 5'-AGTACTCCATAACAATCCAG-3' for human MST2; 5'-GTCCATGGTGACGATCCTCA-3' for human NF2. Following transfection and selection with puromycin, cells were single-cell sorted by fluorescence-activated cell sorting (FACS) into 96-well plate format. Knockout clones were selected by immunoblot analysis, and genomic mutations were confirmed by genome sequencing. Two independent clones were analyzed as indicated.Gene deletion of MEFs by adenoviral infectionSV40 largeT-immortalized Lats1–/–Lats2F/F MEFs were described previously PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (Yu et al. 2012). YAP proteins can be separated into multiple bands in the presence of phos-tag depending on differential phosphorylation levels, with phosphorylated proteins migrating more slowly.AntibodiesAntibodies to YAP (#4912), pYAP (S127 in humans and S112 in mice; #4911), TAZ (#4883), YAP/TAZ (#8418), LATS1 (#3477), LATS2 (#5888), pLATS1/2 (HM; #8654), pLATS1/2 (AL; #9157), MST1 (#3682), NF2 (#12888), pMOB1 (T35; #8699), pERK1/2 (T202/T204; #4370), and ERK1/2 (#4695) were obtained from Cell Signaling; those to YAP (ab52771), MST2 (ab52641), and actin (ab3280) were from Abcam; those to CTGF (sc-14939) and CYR61 (sc-13100) were from Santa Cruz; those to TAZ (#560235) and HSP90 (#610418) were from BD biosciences; those to LATS1 (A300-478A), LATS2 (A300-479A) and AMOT (A303-305A) were from Bethyl Laboratories. GST (13-6700) antibody was from Invitrogen. pAMOT (S175 in humans and S176 in mice) antibody was a gift from Dr. Bin Zhao.ImmunostainingMCF10A cells and MEFs cultured on glass coverslips, were prepared for immunostaining. Cells were fixed for 10 min at room temperature with 4% paraformaldehyde in phosphate-buffered saline (PBS) and were permeabilized with 0.1% Triton X-100 in PBS for 10 min at room temperature. Cells were then incubated consecutively with primary antibodies (overnight at 4°C) and Alexa Fluor 488-labeled goat secondary antibodies (for 90 min at room temperature) in PBS containing 1% bovine serum albumin (BSA). For staining of F-actin, cells were incubated with 6.6 nM Alexa Fluor 488-phalloidin for 90 min after blocking. Cells were covered with a drop of ProLong Gold antifade reagent with DAPI (Invitrogen) for observation.Kinase assayThe immunoprecipitated LATS1 were washed two times with lysis buffer, followed by once with wash buffer (40 mM HEPES pH 7.5, 200 mM NaCl) and once with kinase assay buffer (30 mM HEPES pH 7.5, 50 mM potassium acetate, 5 mM MgCl2). The immunoprecipitates were then subjected to a kinase assay in 30 μl of kinase assay buffer supplemented with 500 μM ATP, and 1 μg of GST-YAP expressed and purified from Escherichia coli as substrates. The reaction mixtures were incubated for 30 min at 30°C, terminated with SDS sample buffer, and subjected to immunoblot analysis. The same procedure was used for MST1 and MST2 kinase assay, except that GST-MOB1A was used as substrates.RNA extraction, reverse transcription (RT), and real-time PCR analysisTotal RNA (1 μg) isolated from cells with the use of RNeasy Plus Mini Kit (Qiagen) was reverse-transcribed to complementary DNA using iScript reverse transcriptase (Bio-Rad). Complementary DNA was then diluted and used for quantification by real-time PCR, which was performed using KAPA SYBR FAST qPCR master mix (Kapa Biosystems) and the 7300 real-time PCR system (Applied Biosystems). The sequences of the PCR primers (forward and reverse, respectively) are 5'-GCAAATTCCATGGCACCGT-3' and 5'-TCGCCCCACTTGATTTTGG-3' for human GAPDH; 5'-GCCTGGAGAAACCTGCCAAGTATG-3' and 5'-GAGTGGGAGTTGCTGTTGAAGTCG-3' for mouse Gapdh; 5'-CCAAGGCTTGACCCTCGTTTTG-3' and 5'-TCGCATCTGTTGCTGCTGGTTG-3' for YAP; 5'-TCACCAACACCAGCAGCAGATG-3' and 5'-GGATTCTCTGAAGCCGCAGTTTC-3' for TAZ; 5'-CCCATTCCAGGGTTTGAGC-3' and 5'-TGCACGAAGAGGTGTTTGTTG-3' for TEAD1; 5'-GCCCGCTACATCAAGCTGA-3' and 5'-TGGTTGCCATTGTCTGGAAAG-3' for TEAD2; 5'-GCCAGTGTCCTGCAGAACAA-3' and 5'-CAAAGGGCTTGATGTCCTGAG-3' for TEAD3; 5'-TCTCTGCCTTCCTGGAGCA-3' and 5'-TCATAGATTTGGCGGATGTCC-3' for TEAD4; 5'-TGCCATTGTTTCCAGAGCCCAG-3' and 5'-GCCACCTTCTCATAGCATCCTTCC-3' for AMOT; 5'-CCTGAGGGAACCGCTTCAAATG-3' and 5'-TGACTCGTATGGAGGAACAGATGGG-3' for human LATS1; 5'-CTTCTCTTCACATCCCTCCTCAAGC-3' and 5'-AGCCTTTATCTCATCAGCACCGTTC-3' for mouse Lats1; 5'-TCATCCACCGAGACATCAAGCC-3' and 5'-TTGTGAGTCCACCTGAACCCAGTG-3' for human LATS2; 5'-ATCCTCCCAAAGGGTACAGCACAG-3' and 5'-TGGTGGCGTCTTGTTCTGGAAG-3' for mouse Lats2; 5'-CCAATGACAACGCCTCCTG-3' and 5'-TGGTGCAGCCAGAAAGCTC-3' for CTGF; 5'-AGCCTCGCATCCTATACAACC-3' and 5'-TTCTTTCACAAGGCGGCACTC-3' for CYR61; 5'-CATACATCCTGTCCGTCCAAGCAG-3' and 5'-TTTCAACTGTTCTCGTCGTTTCCG-3' for MYC; 5'-AGCTTCAACCTCATTGGTGACAGC-3' and 5'-TGAGTTCATTGAGCTGCTCCTGC-3' for NF2. Reactions for GAPDH mRNA were performed concurrently on the same plate as those for the test mRNAs, and results were normalized by the corresponding amount of GAPDH mRNA.Luciferase assayHEK293A cells were seeded in 24-well plates, and pGL3 LATS2-luciferase reporter, pCMV FLAG-YAP, pRK7 Myc-TEAD1, and Renilla plasmids were cotransfected as described above. Luciferase assay was performed 30 h after transfection using the Dual Glo Luciferase System (Promega). All luciferase activities were normalized to Renilla. A 1000-bp fragment of human genomic DNA containing promoter lesion of LATS2 was cloned into the pGL3-Basic vector. Complementary DNA encoding human TEAD1 tagged at its N terminus with Myc was subcloned into pRK7 vectors. The pCMV-Flag-YAP was kindly provided by Dr. Marius Sudol.Chromatin immunoprecipitation (ChIP) assayMCF10A cells were dual crosslinked consecutively with 2 mM disuccinimidyl glutarate (DSG; for 45 min) and 1% formaldehyde (for 10 min), and quenched with 0.125 M glycine for 5 min at room temperature. Harvested cells were washed twice with ice-cold PBS and then lysed in ChIP cell lysis buffer (20 mM Tris-HCl pH 8.0, 85 mM KCl, 0.5% NP-40). The lysates were centrifuged at 2,300 × g for 5 min at 4°C to pellet the nuclei, and the chromatin DNAs were then digested with micrococcal nuclease (MNase) in ChIP MNase buffer (10 mM Tris-HCl pH 7.5, 10 mM NaCl, 2.5 mM MgCl2, 5 mM CaCl2, 0.1% NP-40, 1 mM DTT, 1 mM PMSF, 10,000 gels U/ml MNase). The reaction was stopped by the addition of EDTA to a final concentration of 10 mM, when approximately 80% of genomic DNA was reduced to mononucleosomes. The MNase-digested samples were then sonicated and centrifuged at 16,000 × g for 10 min at 4°C to remove debris, and the resulting supernatants were diluted 1:5 in ChIP dilution buffer (20 mM Tris-HCl pH 8.0, 150 mM NaCl, 1 mM EDTA, 1% Triton-X-100). This material was then used for immunoprecipitation.On day 1, each 2 μg of antibodies to YAP, TEAD1, or normal control rabbit IgG were pre-bound to 50 μl of anti-rabbit or anti-mouse IgG magnetic beads (Invitrogen) overnight at 4°C. On day 2, beads were washed three times with 5 mg/ml BSA/PBS, and immunoprecipitation reactions were carried out with chromatin extracts overnight at 4°C. Five per cent of the chromatin extract was set aside for input. On day 3, beads were washed two times with low salt wash buffer (20 mM Tris-HCl pH 8.0, 150 mM NaCl, 2 mM EDTA, 1% Triton-X-100), followed by twice with high salt wash buffer (20 mM Tris-HCl pH 8.0, 500 mM NaCl, 2 mM EDTA, 1% Triton-X-100), once with LiCl wash buffer (250 mM LiCl, 20 mM Tris-HCl pH 8.0, 1 mM EDTA, 1% NP-40, 1% sodium deoxycholate), and once with TE buffer (100 mM Tris-HCl pH 8.0, 10 mM EDTA). Beads were then resuspended in elution buffer (50 mM Tris-HCl pH 8.0, 10 mM EDTA, 1% SDS) and incubated for 30 min at 65°C with frequent mixing. The resulting eluate and input samples from day 1 were transferred into new tubes, and reverse crosslinking reactions were carried out overnight at 65°C. On day 4, samples were treated with RNase A (0.2 mg/ml) for 1 h at 37°C, followed by proteinase K (0.2 mg/ml) digestion for 2 h at 50°C. DNA was then ethanol-precipitated and purified using the PCR purification kit (Qiagen). Precipitated DNA was quantitated by real-time PCR analysis. The primer sequences for ChIP analysis (forward and reverse, respectively) are 5'-CTTTGGAGAGTTTCAAGAGCC-3' and 5'-TCTGTCCACTGACATACATCC-3' for CTGF; 5'-TTGACTCACCCTGCCCTCAATATC-3' and 5'-TTTCATTCCATCCAGCCTGGGG-3' for GAPDH; 5'-TCCTTCTACGGATGCGGTTGACAG-3' and 5'-ATTCTTGCTTAGCGTTCTTTCCCC-3' for LATS1; 5'-TGGTAACTTGGTGGCTCCTTCAGG-3' and 5'-TTTGCCCTCTCGACTGCATTTG-3' for LATS2-1; 5'-AATACAAATGCAGTCGAGAGGGC-3' and 5'-TCTCGGACCTATTTGACTGGCTG-3' for LATS2-2; 5'-GCCATTTTCAACCTTTTAGCCCC-3' and 5'-TCCTGCCATCCATCAAACAGCC-3' for LATS2-CR1; 5'-TGTTCCGTGCTGATTTCCCTCTG-3' and 5'-ACCAAGGCTTTGTTTTCCCTGG-3' for LATS2-CR2; 5'-CAGCAATTTCATAGGATGCCAGG-3' and 5'-CCTCGTGAGGTTGTTGAATTTCAG-3' for NF2; 5'-ACACAGCACGGACACACACGC-3' and 5'-TTCCCCACCTCAAACCCTGG-3' for NF2-CR. All ChIP signals were normalized to the input (labeled as % of input on the vertical axis).Transwell cell migration assayCell migration assays were performed using BD FalconTM cell culture inserts for 24-well plates with 8 μm pores filter, and the bottom filter was pre-coated with fibronectin (20 μg/ml). HEK293A cells infected with retrovirus encoding tetracycline-inducible Myc-YAP(5SA) construct (or control) were cultured in the presence of doxycycline (200 ng/ml) for 24 h and then were seeded (3 × 104 cells) into the upper chamber of the insert in serum-free media with doxycycline. Lower chamber was filled with complete medium with doxycycline. After 7 h, cells were fixed and stained with 0.1% crystal violet in methanol. Cells in the upper chamber were carefully removed, and cells that migrated through the filter were assessed by photography. 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ADDIN EN.CITE.DATA (Zhang et al. 2010) were bred to Albumin-Cre or Villin-Cre transgenic mice, respectively. Two- to three-month-old sex-matched mice were used for all experimental procedures. For liver-specific YAP transgenic mice, 2-month-old YAP transgenic and non-transgenic littermates were fed 0.2 mg/ml doxycycline (Sigma) in drinking water supplemented with 2.5% sucrose, as described previously PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb25nPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (Dong et al. 2007). Mice were euthanized 2 weeks after induction, and the livers were harvested and immediately frozen in liquid nitrogen. Frozen tissues were pulverized on dry ice, and powdered tissue samples were homogenized in RIPA buffer (20 mM Tris-HCl pH 8.0, 150 mM NaCl, 1% NP-40, 0.5% deoxycholate, 0.1% SDS, 1 mM PMSF, protease inhibitor cocktail, 400 μM Na3VO4, 400 μM EDTA, 10 mM NaF, and 10 mM sodium pyrophosphate) using a tissue tearer. Homogenates were then centrifuged at 16,000 × g for 10 min at 4°C twice to remove debris, and approximately 10 μg of the resulting supernatant proteins were used for immunoblot analysis. Similarly, powdered frozen tissue samples were subjected to RNA extraction. For immunohistochemical staining, tissue samples were prepared as described previously PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFuZzwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (Zhang et al. 2010; Taniguchi et al. 2015). Paraffin-embedded tissue sections were dehydrated followed by antigen retrieval and endogenous peroxidase inactivation. Immunohistochemical staining was performed with the use of Mouse on Mouse (M.O.M.?) Kits (Vector laboratories) according to the manufacturer's protocol. TAZ primary antibody (1:100) was detected using Vectastain elite ABC kit and DAB substrate kit (Vector Laboratories). Hematoxylin was used for nuclear staining.Statistical analysisQuantitative data are presented as mean ± SD and were compared between groups with the two-tailed Student’s t test as performed with Microsoft Excel software. A p value of <0.05 was considered statistically significant. For correlation analysis, gene expression data across a panel of 967 cancer cell lines were downloaded from the Cancer Cell Line Encyclopedia (CCLE) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJyZXRpbmE8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy

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