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

Nat Cell Biol. 2014 Jan;16(1):108-17. doi: 10.1038/ncb2884.

Morvarid Mohseni ¹, Jianlong Sun ¹, Allison Lau ², Stephen Curtis ³, Jeffrey Goldsmith ⁴, Victor L Fox ⁵, Chongjuan Wei ⁶, Marsha Frazier ⁶, Owen Samson ⁷, Kwok-Kin Wong, Carla Kim ³, Fernando D Camargo ¹

Affiliations

1 1] Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA [3] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
2 1] Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
3 1] Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
4 Center for Pediatric Polyposis, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
5 Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
6 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
7 Wnt Signaling and Colorectal Cancer Group, The Beatson Institute for Cancer Research, Cancer Research UK, Glasgow G61 1BD, UK.

PMID: 24362629 DOI: 10.1038/ncb2884

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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