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A genetic screen identifies an LKB1–MARK signalling axis controlling the Hippo–YAP pathway

Nature Cell Biology volume 16, pages 108–117 (2014)Cite this article

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A Corrigendum to this article was published on 31 January 2014

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Abstract

The Hippo–YAP pathway is an emerging signalling cascade involved in the regulation of stem cell activity and organ size. To identify components of this pathway, we performed an RNAi-based kinome screen in human cells. Our screen identified several kinases not previously associated with Hippo signalling that control multiple cellular processes. One of the hits, LKB1, is a common tumour suppressor whose mechanism of action is only partially understood. We demonstrate that LKB1 acts through its substrates of the microtubule affinity-regulating kinase family to regulate the localization of the polarity determinant Scribble and the activity of the core Hippo kinases. Our data also indicate that YAP is functionally important for the tumour suppressive effects of LKB1. Our results identify a signalling axis that links YAP activation with LKB1 mutations, and have implications for the treatment of LKB1-mutant human malignancies. In addition, our findings provide insight into upstream signals of the Hippo–YAP signalling cascade.

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Figure 1: A kinome RNAi screen identifies regulators of Hippo–YAP signalling.
Figure 2: LKB1 regulates YAP activity through the Hippo kinases.
Figure 3: MARKs act downstream of LKB1 to regulate Hippo–YAP.
Figure 4: Scribble acts downstream of LKB1 to regulate Hippo–YAP.
Figure 5: Yap activity is enhanced in Lkb1-deficient tumours.
Figure 6: YAP activation can overcome LKB1-driven tumour suppression.
Figure 7: YAP is essential for the growth of Lkb1-mutant tumours and tissue.

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Change history

  • 07 January 2014

    In the version of this Article originally published, the name ‘Kwok-Kin Wong’ was spelled incorrectly in the author list. This has now been corrected in all online versions of the Article.

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Acknowledgements

We are grateful for stimulating and insightful discussions by members of the Camargo laboratory. Special thanks to R. Bronson of the Harvard Rodent Facility and R. Mathieu of the Stem Cell Program FACS facility. We are grateful to N. Bardeesy for Lkb1 conditional mice. This study was supported by awards from Stand Up to Cancer-AACR initiative (F.D.C.), NIH grant R01 CA131426 (F.D.C.) and DOD 81XWH-10-1-0724. M.M. is a DOD-CDMRP Postdoctoral Fellow. F.D.C. is a Pew Scholar in the Biomedical Sciences.

Author information

Authors and Affiliations

  1. Stem Cell Program, Boston Children’s Hospital, Boston, Massachusetts 02115, USA

    Morvarid Mohseni, Jianlong Sun, Allison Lau, Stephen Curtis, Carla Kim & Fernando D. Camargo

  2. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    Morvarid Mohseni, Jianlong Sun & Fernando D. Camargo

  3. Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA

    Morvarid Mohseni, Jianlong Sun, Allison Lau, Stephen Curtis, Carla Kim & Fernando D. Camargo

  4. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA

    Stephen Curtis & Carla Kim

  5. Center for Pediatric Polyposis, Boston Children’s Hospital, Boston, Massachusetts 02115, USA

    Jeffrey Goldsmith

  6. Division of Gastroenterology and Nutrition, Boston Children’s Hospital, Boston, Massachusetts 02115, USA

    Victor L. Fox

  7. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    Chongjuan Wei & Marsha Frazier

  8. Wnt Signaling and Colorectal Cancer Group, The Beatson Institute for Cancer Research, Cancer Research UK, Glasgow G61 1BD, UK

    Owen Samson

  9. Genetics Division, Department of Medicine Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    Kwok-Kin Wong

  10. Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, Massachusetts 02115, USA

    Kwok-Kin Wong

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Contributions

M.M. and F.D.C. designed the study and wrote the paper. M.M., J.S., A.L. and S.C. performed the experimental work. J.G., V.L.F., C.W. and M.F. provided human clinical tissue. O.S., K-K.W. and C.K. provided mouse tumour samples. C.K. and K-K.W. analysed the data.

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Correspondence to Fernando D. Camargo.

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Integrated supplementary information

Supplementary Figure 1 Identification of kinases that can modulate the Hippo Signaling Pathway in vitro.

(a) Immunofluorescence for YAP localization in confluent HaCaT cells following siRNA transfection of selected kinase hits. Scale bars, 200 μm. Experiment was repeated 3 times independently (b) Western Blot for YAP S127 phosphorylation, and total YAP in 293T cells four days following siRNA transfection of selected kinase hits. Representative blot is shown. This experiment was repeated 3 independent times (c) Mitogen activated kinase pathway siRNA mini-screen using the STBS-luciferase reporter in 293T cells compared to scrambled control (CTR). Data shown is from technical triplicates. The experiment was repeated in three independent experiments. 5 bD) Selective JNK small molecule screen using the STBS-luciferase reporter in 293T cells. Schematic demonstrates where the inhibitors function. Fold changes calculated are compared to untreated controls.

Supplementary Figure 2 LKB1 acts upstream of the Hippo Signaling Pathway in vitro and in vivo.

(a) Knockdown of LKB1 using multiple different siRNA oligos increases STBS-luciferase reporter activity in 293T cells. n = 5 biological replicates ± SD. (b) Knockdown of LKB1 reproducibly increases STBS-luciferase reporter activity across various cell lines. n = 3 biological replicates. Error bars represent mean ± SD. (c) Knockdown of LKB1 reproducibly decreases YAP S127 phosphorylation across various cell lines by western blot analysis. (d) Knockdown of LKB1 in DLD1 cells promotes YAP nuclear localization at confluent cell densities. Experiment has been performed independently three times. Scale bar, 200 μm (e) qPCR validation of LKB1 and YAP siRNA knockdown in 293T cells. n = 3 biological replicates, ± SD. (f) LKB1 activation in W4 cells repressed TEAD-reporter activation. n = 3 replicates per biological triplicate (g) Decreased activity of MST1/2 in LKB1 deficient livers. Ratio of cleaved MST1 versus full length MST is shown for an average from n = 4 mice. (h) Quantification of YAP localization in W4 cells following MST1/2 or LATS1/2 knockdown. Data are derived from three independent experiments where at least 300 cells where scored. N = 3, error bars represent mean ± SD. (i) Validation of MST1/2 and LATS2 downstream of LKB1 using two additional sets of siRNAS. Representative figure from three independent experiments is shown. Scale bars, 20 μm (j, k) Immunoprecipitation of overexpressed LKB1, LATS1, and MST1 in 293T cells. Representative blot is shown. Experiment has been performed three times independently. Error bars represent mean ± SD from triplicate samples. **P<0.01, two-tailed t-test.

Supplementary Figure 3 Yap1 activity and localization is dependent on the LKB1 substrate, MARKs.

(a) qPCR validation of siRNA knockdown of MARK1 and MARK4 and expression of YAP-target genes, CTGF and CYR61. n = 3 biological replicates (b) STBS reporter activity following knockdown of MARK4 and YAP in 293T cells. n = 3 biological replicates (c) Western blot showing expression level of Mob1/LATS1/LATS2 in MARK4 knockdown cells. Representative blot is shown from three independent experiments (d) Activation of LKB1 in W4 cells promotes activation of MARKs as measured by Thr215 phosphorylation (MARK1) in the kinase activation loop. Representative blot is shown from three independent experiments (e) Immunofluorescence for YAP localization (green) and cell polarization (red) in doxycycline-untreated W4 cells following knockdown of MARK4. N = 3 biological replicates. Each experiment was performed with technical triplicates. Scale bar, 20 μm. (f) YAP localization in W4 cells following LKB1 activation and knockdown of MARK4 using 2 independent siRNA’s. Three independent experiments were performed. Scale bars, 20 μm. (g) Biochemical analysis of phospho-YAP localization by subcellular fractionation of W4 cells treated with doxycycline and MARK knockdown. Representative blot from three independent experiments is shown. Error bars represent mean ± SD.

Supplementary Figure 4 Scribble expression and correct localization is required for Yap1 activity.

(a) Immunofluorescence for Scribble (SCRIB) localization (green) in DLD1 cells following LKB1 and MARK siRNA knockdown. Experiment was repeated three times. Scale bar, 200 μm. (b-c) Immunoblot and qPCR for SCRIB expression following LKB1 and MARK1 knockdown in MCF7 cells. n = 3 biological triplicates (d) siRNA knockdown of SCRIB in 293T cells induces TEAD-reporter activity. n = 3 independent experiments. (e) qPCR validation of SCRIB knockdown using 3 independent siRNA’s. n = 3 independent experiments. (f) Immunofluorescence for YAP localization (green) and cell polarization (red) in doxycycline-untreated W4 cells following knockdown of SCRIB. Biological replicates were performed three times. Scale bar, 20 μm. (g) Quantification of YAP localization in W4 cells following scribble knockdown. Data are derived from three independent experiments where at least 300 cells where scored. (h) Immunofluorescence for YAP localization following activation of LKB1 and knockdown of scribble using 2 independent siRNA’s. Scale bar 20 μm. (i) Immunoprecipitation of overexpressed MARK4 with SCRIB, LKB1, MST1, and LATS1. Experiment was repeated three times. (j) Immunoprecipitated SCRIB in MARK1-knockdown cells show decreased interaction with MST and LATS. Experiment was repeated three times. Error bars represent mean ± SD.

Supplementary Figure 5 Generation of a Hippo Gene Expression Signature and localization of Yap in human LKB1-mutant tissues.

(a) Microarray analysis on three different cancer cell lines reveal a core set of genes whose expression changes following siRNA knockdown of NF2 + LATS1/2, and for which this response is dependent on YAP/TAZ. Differentially expressed genes were defined as those with at least 2 fold change in NF2/LATS2 double knockdown cells and a p value smaller than 0.05. (b) YAP immunohistochemistry on human SMAD4 juvenille polyposis (JP) intestinal polyp compared to a human LKB1 mutant Peutz-Jeghers (PJ) intestinal polyp. Scale bar, 500 μm.

Supplementary Figure 6 Yap1 acts downstream of LKB1 and can overcome LKB1 tumor suppressive function.

(a) Quantification of triplicate samples of number and size of W4, W4TetOYAP, +/- doxycycline colonies in soft agar assays. n = 3 biological triplicates (b) Tumor weights of W4, W4TetOYAP, +/- doxycycline after seven weeks. Representative images of nude mice carrying xenografts with W4, W4TetOYAP tumors. N = 7 mice per each of the four genotypes. (c) qPCR validation of shRNA knockdown of LATS2 and activation of YAP-target genes in W4 cells. N = 3 biological replicates. (d) qPCR of Scribble following Scribble siRNA knockdown in the presence of LKB1 activation. n = 3 biological replicates. Error bars represent mean ± SD.

Supplementary Figure 7 Loss of Yap1 in LKB1 mutant xenograft show tumor growth inhibition.

(a) Quantification of triplicate samples of number and size of W4, W4TetOYAP, +/- doxycycline colonies. n = 3 biological replicates (b-c) Average tumor size and number per mouse following intravenous injection of 1×106 A549iYAPshRNA cells (-/+ doxycycline) for 6 weeks. n = 3 mice per group (d-f) Two cell lines that are low in YAP target gene expression were infected with shYAP1 hairpins and assessed for proliferation using MTS assays (e) and soft agar colony formation assay (f) n = 3 biological replicates. Scale bar, 500 μm. (g) Expression levels of LKB1 and YAP following Ad-cre administration in Lkb1-floxed and Lkb1/YAP floxed livers. n = 4 mice per genotype. Error bars represent mean ± SD.

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Mohseni, M., Sun, J., Lau, A. et al. A genetic screen identifies an LKB1–MARK signalling axis controlling the Hippo–YAP pathway. Nat Cell Biol 16, 108–117 (2014). https://doi.org/10.1038/ncb2884

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