CAMP/PKA signalling reinforces the LATS-YAP pathway to fully suppress YAP in response to actin cytoskeletal changes

Minchul Kim, Miju Kim, Seunghee Lee, Shinji Kuninaka, Hideyuki Saya, Ho Lee, Soo-Kyung Lee, Dae Sik Lim

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Actin cytoskeletal damage induces inactivation of the oncoprotein YAP (Yes-associated protein). It is known that the serine/threonine kinase LATS (large tumour suppressor) inactivates YAP by phosphorylating its Ser127 and Ser381 residues. However, the events downstream of actin cytoskeletal changes that are involved in the regulation of the LATS-YAP pathway and the mechanism by which LATS differentially phosphorylates YAP on Ser127 and Ser381 in vivo have remained elusive. Here, we show that cyclic AMP (cAMP)-dependent protein kinase (PKA) phosphorylates LATS and thereby enhances its activity sufficiently to phosphorylate YAP on Ser381. We also found that PKA activity is involved in all contexts previously reported to trigger the LATS-YAP pathway, including actin cytoskeletal damage, G-protein-coupled receptor activation, and engagement of the Hippo pathway. Inhibition of PKA and overexpression of YAP cooperate to transform normal cells and amplify neural progenitor pools in developing chick embryos. We also implicate neurofibromin 2 as an AKAP (A-kinase-anchoring protein) scaffold protein that facilitates the function of the cAMP/PKA-LATS-YAP pathway. Our study thus incorporates PKA as novel component of the Hippo pathway.

Original languageEnglish (US)
Pages (from-to)1543-1555
Number of pages13
JournalEMBO Journal
Volume32
Issue number11
DOIs
StatePublished - May 29 2013
Externally publishedYes

Fingerprint

Protein Kinases
Actins
Tumors
Neoplasms
Proteins
Neurofibromin 2
Adenylate Kinase
Protein-Serine-Threonine Kinases
Oncogene Proteins
Chick Embryo
G-Protein-Coupled Receptors
Cyclic AMP-Dependent Protein Kinases
Cyclic AMP
Scaffolds
Phosphotransferases
Chemical activation

Keywords

  • Actin cytoskeleton
  • camp
  • Hippo pathway
  • Pka

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

Cite this

CAMP/PKA signalling reinforces the LATS-YAP pathway to fully suppress YAP in response to actin cytoskeletal changes. / Kim, Minchul; Kim, Miju; Lee, Seunghee; Kuninaka, Shinji; Saya, Hideyuki; Lee, Ho; Lee, Soo-Kyung; Lim, Dae Sik.

In: EMBO Journal, Vol. 32, No. 11, 29.05.2013, p. 1543-1555.

Research output: Contribution to journalArticle

Kim, Minchul ; Kim, Miju ; Lee, Seunghee ; Kuninaka, Shinji ; Saya, Hideyuki ; Lee, Ho ; Lee, Soo-Kyung ; Lim, Dae Sik. / CAMP/PKA signalling reinforces the LATS-YAP pathway to fully suppress YAP in response to actin cytoskeletal changes. In: EMBO Journal. 2013 ; Vol. 32, No. 11. pp. 1543-1555.
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