Hippo kinases LATS1/2 control human breast cell fate via crosstalk with ERα
| Autor: | Christina Scheel, Zsuzsanna Varga, Michael B. Stadler, Mohamed Bentires-Alj, Sungeun Kim, Daniela Kaup, Kirsten D. Mertz, Adrian Britschgi, Shany Koren, Heike Brinkhaus, Alexandra Vissieres, Ghislain M. C. Bonamy, Joana Pinto Couto, Hans Voshol, Tim Roloff, Stephan Duss, Loren Miraglia, Duvini De Silva, Cédric Leroy, Venkateshwar A. Reddy, Anthony P. Orth |
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| Přispěvatelé: | University of Zurich, Bentires-Alj, Mohamed |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Proteasome Endopeptidase Complex medicine.medical_specialty Ubiquitin-Protein Ligases Cellular differentiation 610 Medicine & health Cell fate determination Biology Protein Serine-Threonine Kinases Article 03 medical and health sciences Breast cancer 10049 Institute of Pathology and Molecular Pathology Internal medicine medicine Humans Cell Lineage Genes Tumor Suppressor Hippo Signaling Pathway Breast Progenitor cell skin and connective tissue diseases Transcription factor Cells Cultured Adaptor Proteins Signal Transducing 1000 Multidisciplinary Hippo signaling pathway Multidisciplinary Ubiquitin Tumor Suppressor Proteins Myoepithelial cell Estrogen Receptor alpha YAP-Signaling Proteins Cell Differentiation Phosphoproteins medicine.disease Research Highlight 3. Good health Cell biology 030104 developmental biology Endocrinology Proteolysis Female Stem cell Carrier Proteins Transcription Factors Signal Transduction |
| Zdroj: | Nature Nature 541, 541-545 (2017) |
| Popis: | Cell fate perturbations underlie many human diseases, including breast cancer(1,2). Unfortunately, the mechanisms by which breast cell fate are regulated are largely unknown. The mammary gland epithelium consists of differentiated luminal epithelial and basal myoepithelial cells, as well as undifferentiated stem cells and more restricted progenitors(3,4). Breast cancer originates from this epithelium, but the molecular mechanisms that underlie breast epithelial hierarchy remain ill-defined. Here, we use a high-content confocal image-based short hairpin RNA screen to identify tumour suppressors that regulate breast cell fate in primary human breast epithelial cells. We show that ablation of the large tumour suppressor kinases (LATS) 1 and 2 (refs 5, 6), which are part of the Hippo pathway, promotes the luminal phenotype and increases the number of bipotent and luminal progenitors, the proposed cells-of-origin of most human breast cancers. Mechanistically, we have identified a direct interaction between Hippo and oestrogen receptor-alpha (ER alpha) signalling. In the presence of LATS, ERa was targeted for ubiquitination and Ddb1-cullin4-associated-factor 1 (DCAF1)-dependent proteasomal degradation. Absence of LATS stabilized ERa and the Hippo effectors YAP and TAZ (hereafter YAP/TAZ), which together control breast cell fate through intrinsic and paracrine mechanisms. Our findings reveal a non-canonical (that is, YAP/TAZ-independent) effect of LATS in the regulation of human breast cell fate. |
| Databáze: | OpenAIRE |
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