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. Epub 2013 Dec 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Line, Tumor
  • Enzyme Activation
  • Gene Knockdown Techniques
  • Genes, Reporter
  • Genetic Testing*
  • HEK293 Cells
  • Humans
  • Mice
  • Mutation / genetics
  • Neoplasms / enzymology
  • Neoplasms / pathology
  • Phosphoproteins / metabolism*
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • Signal Transduction* / genetics
  • Substrate Specificity
  • Transcription Factors

Substances

  • Adaptor Proteins, Signal Transducing
  • Phosphoproteins
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • MARK1 protein, human
  • STK11 protein, human
  • Stk11 protein, mouse
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases