YAP regulates cell size and growth dynamics via non-cell autonomous mediators

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

The following data sets were generated

Article and author information

Author details

  1. Douaa Mugahid

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Marian Kalocsay

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Xili Liu

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jonathan Scott Gruver

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Leonid Peshkin

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6420-848X
  6. Marc W Kirschner

    Department of Systems Biology, Harvard Medical School, Boston, United States
    For correspondence
    marc@hms.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6540-6130

Funding

Harvard Medical School (Dean's Innovation Grant)

  • Marc W Kirschner

National Institute of General Medical Sciences (GM026875)

  • 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

  1. Duojia Pan, UT Southwestern Medical Center and HHMI, United States

Version history

  1. Received: November 7, 2019
  2. Accepted: December 16, 2019
  3. Accepted Manuscript published: January 8, 2020 (version 1)
  4. Accepted Manuscript updated: January 9, 2020 (version 2)
  5. Version of Record published: January 29, 2020 (version 3)
  6. 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

  • 6,140
    views
  • 761
    downloads
  • 29
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

  1. Douaa Mugahid
  2. Marian Kalocsay
  3. Xili Liu
  4. Jonathan Scott Gruver
  5. Leonid Peshkin
  6. Marc W Kirschner
(2020)
YAP regulates cell size and growth dynamics via non-cell autonomous mediators
eLife 9:e53404.
https://doi.org/10.7554/eLife.53404

Share this article

https://doi.org/10.7554/eLife.53404

Further reading

    1. Cell Biology
    2. Genetics and Genomics
    Yangzi Zhao, Lijun Ren ... Zhukuan Cheng
    Research Article

    Cohesin is a multi-subunit protein that plays a pivotal role in holding sister chromatids together during cell division. Sister chromatid cohesion 3 (SCC3), constituents of cohesin complex, is highly conserved from yeast to mammals. Since the deletion of individual cohesin subunit always causes lethality, it is difficult to dissect its biological function in both mitosis and meiosis. Here, we obtained scc3 weak mutants using CRISPR-Cas9 system to explore its function during rice mitosis and meiosis. The scc3 weak mutants displayed obvious vegetative defects and complete sterility, underscoring the essential roles of SCC3 in both mitosis and meiosis. SCC3 is localized on chromatin from interphase to prometaphase in mitosis. However, in meiosis, SCC3 acts as an axial element during early prophase I and subsequently situates onto centromeric regions following the disassembly of the synaptonemal complex. The loading of SCC3 onto meiotic chromosomes depends on REC8. scc3 shows severe defects in homologous pairing and synapsis. Consequently, SCC3 functions as an axial element that is essential for maintaining homologous chromosome pairing and synapsis during meiosis.

    1. Cell Biology
    2. Physics of Living Systems
    Ivan Castello-Serrano, Frederick A Heberle ... Ilya Levental
    Research Article

    The organelles of eukaryotic cells maintain distinct protein and lipid compositions required for their specific functions. The mechanisms by which many of these components are sorted to their specific locations remain unknown. While some motifs mediating subcellular protein localization have been identified, many membrane proteins and most membrane lipids lack known sorting determinants. A putative mechanism for sorting of membrane components is based on membrane domains known as lipid rafts, which are laterally segregated nanoscopic assemblies of specific lipids and proteins. To assess the role of such domains in the secretory pathway, we applied a robust tool for synchronized secretory protein traffic (RUSH, Retention Using Selective Hooks) to protein constructs with defined affinity for raft phases. These constructs consist solely of single-pass transmembrane domains (TMDs) and, lacking other sorting determinants, constitute probes for membrane domain-mediated trafficking. We find that while raft affinity can be sufficient for steady-state PM localization, it is not sufficient for rapid exit from the endoplasmic reticulum (ER), which is instead mediated by a short cytosolic peptide motif. In contrast, we find that Golgi exit kinetics are highly dependent on raft affinity, with raft preferring probes exiting the Golgi ~2.5-fold faster than probes with minimal raft affinity. We rationalize these observations with a kinetic model of secretory trafficking, wherein Golgi export can be facilitated by protein association with raft domains. These observations support a role for raft-like membrane domains in the secretory pathway and establish an experimental paradigm for dissecting its underlying machinery.