Phase separation of Hippo signalling complexes

Author:

Bonello Teresa T1,Cai Danfeng23,Fletcher Georgina C4,Wiengartner Kyler3,Pengilly Victoria1,Lange Kimberly S3,Liu Zhe2,Lippincott‐Schwartz Jennifer2,Kavran Jennifer M35,Thompson Barry J14ORCID

Affiliation:

1. EMBL Australia, John Curtin School of Medical Research Australian National University Canberra ACT Australia

2. HHMI Janelia Research Campus Ashburn VA USA

3. Department of Biochemistry and Molecular Biology Bloomberg School of Public Health Baltimore MD USA

4. Epithelial Biology Laboratory The Francis Crick Institute London UK

5. Department of Biophysics and Biophysical Chemistry, and Department of Oncology Johns Hopkins School of Medicine Baltimore MD USA

Abstract

AbstractThe Hippo pathway was originally discovered to control tissue growth inDrosophilaand includes the Hippo kinase (Hpo; MST1/2 in mammals), scaffold protein Salvador (Sav; SAV1 in mammals) and the Warts kinase (Wts; LATS1/2 in mammals). The Hpo kinase is activated by binding to Crumbs‐Expanded (Crb‐Ex) and/or Merlin‐Kibra (Mer‐Kib) proteins at the apical domain of epithelial cells. Here we show that activation of Hpo also involves the formation of supramolecular complexes with properties of a biomolecular condensate, including concentration dependence and sensitivity to starvation, macromolecular crowding, or 1,6‐hexanediol treatment. Overexpressing Ex or Kib induces formation of micron‐scale Hpo condensates in the cytoplasm, rather than at the apical membrane. Several Hippo pathway components contain unstructured low‐complexity domains and purified Hpo‐Sav complexes undergo phase separationin vitro. Formation of Hpo condensates is conserved in human cells. We propose that apical Hpo kinase activation occurs in phase separated “signalosomes” induced by clustering of upstream pathway components.

Funder

Australian Research Council

EMBL Australia

Howard Hughes Medical Institute

Australian National University

Publisher

Springer Science and Business Media LLC

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Molecular Biology,General Neuroscience

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