Signaling proteins in HSC fate determination are unequally segregated during asymmetric cell division

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Abstract

Ugale et al. demonstrate that CDC42, ERK, and mTORC1 signaling are polarized in premitotic hematopoietic stem cells and unequally segregated during asymmetric cell division. A CDC42/ERK/mTORC1 pathway maintains HSC polarity and balances symmetric and asymmetric cell division.

Abstract

Hematopoietic stem cells (HSCs) continuously replenish mature blood cells with limited lifespans. To maintain the HSC compartment while ensuring output of differentiated cells, HSCs undergo asymmetric cell division (ACD), generating two daughter cells with different fates: one will proliferate and give rise to the differentiated cells’ progeny, and one will return to quiescence to maintain the HSC compartment. A balance between MEK/ERK and mTORC1 pathways is needed to ensure HSC homeostasis. Here, we show that activation of these pathways is spatially segregated in premitotic HSCs and unequally inherited during ACD. A combination of genetic and chemical perturbations shows that an ERK-dependent mechanism determines the balance between pathways affecting polarity, proliferation, and metabolism, and thus determines the frequency of asymmetrically dividing HSCs. Our data identify druggable targets that modulate HSC fate determination at the level of asymmetric division.

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Most cited references 49

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FlowSOM: Using self-organizing maps for visualization and interpretation of cytometry data.

Sofie Van Gassen, Britt Callebaut, Mary J Van Helden … (2015)

The number of markers measured in both flow and mass cytometry keeps increasing steadily. Although this provides a wealth of information, it becomes infeasible to analyze these datasets manually. When using 2D scatter plots, the number of possible plots increases exponentially with the number of markers and therefore, relevant information that is present in the data might be missed. In this article, we introduce a new visualization technique, called FlowSOM, which analyzes Flow or mass cytometry data using a Self-Organizing Map. Using a two-level clustering and star charts, our algorithm helps to obtain a clear overview of how all markers are behaving on all cells, and to detect subsets that might be missed otherwise. R code is available at https://github.com/SofieVG/FlowSOM and will be made available at Bioconductor.

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Lysosomes as dynamic regulators of cell and organismal homeostasis

Andrea Ballabio, Juan Bonifacino (2019)

Exciting new discoveries have transformed the view of the lysosome from a static organelle dedicated to the disposal and recycling of cellular waste to a highly dynamic structure that mediates the adaptation of cell metabolism to environmental cues. Lysosome-mediated signalling pathways and transcription programmes are able to sense the status of cellular metabolism and control the switch between anabolism and catabolism by regulating lysosomal biogenesis and autophagy. The lysosome also extensively communicates with other cellular structures by exchanging content and information and by establishing membrane contact sites. It is now clear that lysosome positioning is a dynamically regulated process and a crucial determinant of lysosomal function. Finally, growing evidence indicates that the role of lysosomal dysfunction in human diseases goes beyond rare inherited diseases, such as lysosomal storage disorders, to include common neurodegenerative and metabolic diseases, as well as cancer. Together, these discoveries highlight the lysosome as a regulatory hub for cellular and organismal homeostasis, and an attractive therapeutic target for a broad variety of disease conditions.

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RAS-targeted therapies: is the undruggable drugged?

Amanda R. Moore, Scott C. Rosenberg, Frank McCormick … (2020)

RAS ( KRAS , NRAS and HRAS ) is the most frequently mutated gene family in cancers, and, consequently, investigators have sought an effective RAS inhibitor for more than three decades. Even 10 years ago, RAS inhibitors were so elusive that RAS was termed ‘undruggable’. Now, with the success of allele-specific covalent inhibitors against the most frequently mutated version of RAS in non-small-cell lung cancer, KRAS G12C , we have the opportunity to evaluate the best therapeutic strategies to treat RAS-driven cancers. Mutation-specific biochemical properties, as well as the tissue of origin, are likely to affect the effectiveness of such treatments. Currently, direct inhibition of mutant RAS through allele-specific inhibitors provides the best therapeutic approach. Therapies that target RAS-activating pathways or RAS effector pathways could be combined with these direct RAS inhibitors, immune checkpoint inhibitors or T cell-targeting approaches to treat RAS -mutant tumours. Here we review recent advances in therapies that target mutant RAS proteins and discuss the future challenges of these therapies, including combination strategies.

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Author and article information

Contributors

Amol Ugale:

ORCID: https://orcid.org/0009-0005-6553-987X

Role: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Dhanlakshmi Shunmugam:

ORCID: https://orcid.org/0009-0002-5126-0622

Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Lokesh G. Pimpale:

ORCID: https://orcid.org/0000-0001-6145-1516

Role: Data curationRole: Formal analysisRole: SoftwareRole: ValidationRole: Visualization

Elisabeth Rebhan:

ORCID: https://orcid.org/0009-0006-3239-1351

Role: InvestigationRole: Methodology

Manuela Baccarini:

ORCID: https://orcid.org/0000-0002-3033-391X

Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing - review & editing

Journal

Journal ID (nlm-ta): J Cell Biol

Journal ID (iso-abbrev): J Cell Biol

Journal ID (publisher-id): jcb

Title: The Journal of Cell Biology

Publisher: Rockefeller University Press

ISSN (Print): 0021-9525

ISSN (Electronic): 1540-8140

Publication date Collection: 02 September 2024

Publication date (Electronic): 14 June 2024

Publication date PMC-release: 14 June 2024

Volume: 223

Issue: 9

Electronic Location Identifier: e202310137

Affiliations

[1 ]Department of Microbiology, Max Perutz Labs Vienna, University of Vienna, Immunobiology and Genetics ( https://ror.org/03prydq77) , Vienna, Austria

[2 ]Vienna BioCenter PhD Program, Doctoral School of the University of Vienna and Medical University of Vienna ( https://ror.org/03prydq77) , Vienna, Austria

[3 ]HeartBeat.bio AG; , Vienna, Austria

Author notes

Correspondence to Manuela Baccarini: manuela.baccarini@ 123456univie.ac.at

Disclosures: The authors declare no competing interests exist.

E. Rebhan’s current affiliation is Salzkammergutklinikum Vöcklabruck, Department of Pathology, Vöcklabruck, Austria.

Author information

Amol Ugale https://orcid.org/0009-0005-6553-987X

Dhanlakshmi Shunmugam https://orcid.org/0009-0002-5126-0622

Lokesh G. Pimpale https://orcid.org/0000-0001-6145-1516

Elisabeth Rebhan https://orcid.org/0009-0006-3239-1351

Manuela Baccarini https://orcid.org/0000-0002-3033-391X

Article

Publisher ID: jcb.202310137

DOI: 10.1083/jcb.202310137

PMC ID: 11178505

PubMed ID: 38874393

SO-VID: 7478a4af-539e-4e69-9791-4bceb7652e27

License:

This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

History

Date received : 27 October 2023

Date revision received : 21 March 2024

Date accepted : 13 May 2024

Funding

Funded by: Austrian Science Fund, DOI http://dx.doi.org/10.13039/501100002428;

Award ID: P 31744

Funded by: Swedish Research Council, DOI http://dx.doi.org/10.13039/501100004359;

Award ID: 2017-06394

Funded by: University of Vienna, DOI http://dx.doi.org/10.13039/501100003065;

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Signaling proteins in HSC fate determination are unequally segregated during asymmetric cell division

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Stress signalling in stem cells

Most cited references 49

FlowSOM: Using self-organizing maps for visualization and interpretation of cytometry data.

Lysosomes as dynamic regulators of cell and organismal homeostasis

RAS-targeted therapies: is the undruggable drugged?

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