YAP regulates cell size and growth dynamics via non-cell autonomous mediators
- Harvard Medical School, United States
Abstract
The Hippo pathway regulates organ size, regeneration, and cell growth by controlling the stability of the transcription factor, YAP (Yorkie in Drosophila). When there is tissue damage, YAP is activated allowing the restoration of homeostatic tissue size. The exact signals by which YAP is activated are still not fully understood, but its activation is known to affect both cell size and cell number. Here we used cultured cells to examine the coordinated regulation of cell size and number under the control of YAP. Our experiments in isogenic HEK293 cells reveal that YAP can affect cell size and number by independent circuits. Some of these effects are cell autonomous, such as proliferation, while others are mediated by secreted signals. In particular CYR61, a known secreted YAP target, is a non-cell autonomous mediator of cell survival, while another unidentified secreted factor controls cell size.
Data availability
Sequencing data has been deposited in GEO under accession code GSE123296
-
Induction of YAP5SA-GFP vs nGFP expression in FlipinTrex293 cellsNCBI Gene Expression Omnibus, GSE123296.
Article and author information
Author details
Funding
Harvard Medical School (Dean's Innovation Grant)
- Marc W Kirschner
National Institute of General Medical Sciences (GM026875)
- Marc W Kirschner
Eunice Kennedy Shriver National Institute of Child Health and Human Development (9R01HD091846-05A1)
- Marc W Kirschner
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Duojia Pan, UT Southwestern Medical Center and HHMI, United States
Version history
- Received: November 7, 2019
- Accepted: December 16, 2019
- Accepted Manuscript published: January 8, 2020 (version 1)
- Accepted Manuscript updated: January 9, 2020 (version 2)
- Version of Record published: January 29, 2020 (version 3)
- Version of Record updated: January 30, 2020 (version 4)
Copyright
© 2020, Mugahid et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 5,825
- Page views
-
- 728
- Downloads
-
- 22
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
YAP regulates cell size and growth dynamics via non-cell autonomous mediators
eLife 9:e53404.
https://doi.org/10.7554/eLife.53404
Further reading
-
- Biochemistry and Chemical Biology
- Cell Biology
The ATPase p97 (also known as VCP, Cdc48) has crucial functions in a variety of important cellular processes such as protein quality control, organellar homeostasis, and DNA damage repair, and its de-regulation is linked to neuromuscular diseases and cancer. p97 is tightly controlled by numerous regulatory cofactors, but the full range and function of the p97–cofactor network is unknown. Here, we identify the hitherto uncharacterized FAM104 proteins as a conserved family of p97 interactors. The two human family members VCP nuclear cofactor family member 1 and 2 (VCF1/2) bind p97 directly via a novel, alpha-helical motif and associate with p97-UFD1-NPL4 and p97-UBXN2B complexes in cells. VCF1/2 localize to the nucleus and promote the nuclear import of p97. Loss of VCF1/2 results in reduced nuclear p97 levels, slow growth, and hypersensitivity to chemical inhibition of p97 in the absence and presence of DNA damage, suggesting that FAM104 proteins are critical regulators of nuclear p97 functions.
-
- Cell Biology
- Neuroscience
The amyloid beta (Aβ) plaques found in Alzheimer’s disease (AD) patients’ brains contain collagens and are embedded extracellularly. Several collagens have been proposed to influence Aβ aggregate formation, yet their role in clearance is unknown. To investigate the potential role of collagens in forming and clearance of extracellular aggregates in vivo, we created a transgenic Caenorhabditis elegans strain that expresses and secretes human Aβ1-42. This secreted Aβ forms aggregates in two distinct places within the extracellular matrix. In a screen for extracellular human Aβ aggregation regulators, we identified different collagens to ameliorate or potentiate Aβ aggregation. We show that a disintegrin and metalloprotease a disintegrin and metalloprotease 2 (ADM-2), an ortholog of ADAM9, reduces the load of extracellular Aβ aggregates. ADM-2 is required and sufficient to remove the extracellular Aβ aggregates. Thus, we provide in vivo evidence of collagens essential for aggregate formation and metalloprotease participating in extracellular Aβ aggregate removal.
