The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling

BACKGROUND: Cell-to-cell heterogeneity is an inherent feature of multicellular organisms and is central in all physiological and pathophysiological processes including cellular signal transduction. The cytokine IL-6 is an essential mediator of pro- and anti-inflammatory processes. Dysregulated IL-6-...

Descripción completa

Detalles Bibliográficos
Autores principales: Fiebelkow, Jessica, Guendel, André, Guendel, Beate, Mehwald, Nora, Jetka, Tomasz, Komorowski, Michal, Waldherr, Steffen, Schaper, Fred, Dittrich, Anna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444181/
https://www.ncbi.nlm.nih.gov/pubmed/34530865
http://dx.doi.org/10.1186/s12964-021-00770-7
_version_ 1784568436821590016
author Fiebelkow, Jessica
Guendel, André
Guendel, Beate
Mehwald, Nora
Jetka, Tomasz
Komorowski, Michal
Waldherr, Steffen
Schaper, Fred
Dittrich, Anna
author_facet Fiebelkow, Jessica
Guendel, André
Guendel, Beate
Mehwald, Nora
Jetka, Tomasz
Komorowski, Michal
Waldherr, Steffen
Schaper, Fred
Dittrich, Anna
author_sort Fiebelkow, Jessica
collection PubMed
description BACKGROUND: Cell-to-cell heterogeneity is an inherent feature of multicellular organisms and is central in all physiological and pathophysiological processes including cellular signal transduction. The cytokine IL-6 is an essential mediator of pro- and anti-inflammatory processes. Dysregulated IL-6-induced intracellular JAK/STAT signalling is associated with severe inflammatory and proliferative diseases. Under physiological conditions JAK/STAT signalling is rigorously controlled and timely orchestrated by regulatory mechanisms such as expression of the feedback-inhibitor SOCS3 and activation of the protein-tyrosine phosphatase SHP2 (PTPN11). Interestingly, the function of negative regulators seems not to be restricted to controlling the strength and timely orchestration of IL-6-induced STAT3 activation. Exemplarily, SOCS3 increases robustness of late IL-6-induced STAT3 activation against heterogenous STAT3 expression and reduces the amount of information transferred through JAK/STAT signalling. METHODS: Here we use multiplexed single-cell analyses and information theoretic approaches to clarify whether also SHP2 contributes to robustness of STAT3 activation and whether SHP2 affects the amount of information transferred through IL-6-induced JAK/STAT signalling. RESULTS: SHP2 increases robustness of both basal, cytokine-independent STAT3 activation and early IL-6-induced STAT3 activation against differential STAT3 expression. However, SHP2 does not affect robustness of late IL-6-induced STAT3 activation. In contrast to SOCS3, SHP2 increases the amount of information transferred through IL-6-induced JAK/STAT signalling, probably by reducing cytokine-independent STAT3 activation and thereby increasing sensitivity of the cells. These effects are independent of SHP2-dependent MAPK activation. CONCLUSION: In summary, the results of this study extend our knowledge of the functions of SHP2 in IL-6-induced JAK/STAT signalling. SHP2 is not only a repressor of basal and cytokine-induced STAT3 activity, but also ensures robustness and transmission of information. [Image: see text] Plain English summary Cells within a multicellular organism communicate with each other to exchange information about the environment. Communication between cells is facilitated by soluble molecules that transmit information from one cell to the other. Cytokines such as interleukin-6 are important soluble mediators that are secreted when an organism is faced with infections or inflammation. Secreted cytokines bind to receptors within the membrane of their target cells. This binding induces activation of an intracellular cascade of reactions called signal transduction, which leads to cellular responses. An important example of intracellular signal transduction is JAK/STAT signalling. In healthy organisms signalling is controlled and timed by regulatory mechanisms, whose activation results in a controlled shutdown of signalling pathways. Interestingly, not all cells within an organism are identical. They differ in the amount of proteins involved in signal transduction, such as STAT3. These differences shape cellular communication and responses to intracellular signalling. Here, we show that an important negative regulatory protein called SHP2 (or PTPN11) is not only responsible for shutting down signalling, but also for steering signalling in heterogeneous cell populations. SHP2 increases robustness of STAT3 activation against variable STAT3 amounts in individual cells. Additionally, it increases the amount of information transferred through JAK/STAT signalling by increasing the dynamic range of pathway activation in heterogeneous cell populations. This is an amazing new function of negative regulatory proteins that contributes to communication in heterogeneous multicellular organisms in health and disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-021-00770-7.
format Online
Article
Text
id pubmed-8444181
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-84441812021-09-16 The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling Fiebelkow, Jessica Guendel, André Guendel, Beate Mehwald, Nora Jetka, Tomasz Komorowski, Michal Waldherr, Steffen Schaper, Fred Dittrich, Anna Cell Commun Signal Research BACKGROUND: Cell-to-cell heterogeneity is an inherent feature of multicellular organisms and is central in all physiological and pathophysiological processes including cellular signal transduction. The cytokine IL-6 is an essential mediator of pro- and anti-inflammatory processes. Dysregulated IL-6-induced intracellular JAK/STAT signalling is associated with severe inflammatory and proliferative diseases. Under physiological conditions JAK/STAT signalling is rigorously controlled and timely orchestrated by regulatory mechanisms such as expression of the feedback-inhibitor SOCS3 and activation of the protein-tyrosine phosphatase SHP2 (PTPN11). Interestingly, the function of negative regulators seems not to be restricted to controlling the strength and timely orchestration of IL-6-induced STAT3 activation. Exemplarily, SOCS3 increases robustness of late IL-6-induced STAT3 activation against heterogenous STAT3 expression and reduces the amount of information transferred through JAK/STAT signalling. METHODS: Here we use multiplexed single-cell analyses and information theoretic approaches to clarify whether also SHP2 contributes to robustness of STAT3 activation and whether SHP2 affects the amount of information transferred through IL-6-induced JAK/STAT signalling. RESULTS: SHP2 increases robustness of both basal, cytokine-independent STAT3 activation and early IL-6-induced STAT3 activation against differential STAT3 expression. However, SHP2 does not affect robustness of late IL-6-induced STAT3 activation. In contrast to SOCS3, SHP2 increases the amount of information transferred through IL-6-induced JAK/STAT signalling, probably by reducing cytokine-independent STAT3 activation and thereby increasing sensitivity of the cells. These effects are independent of SHP2-dependent MAPK activation. CONCLUSION: In summary, the results of this study extend our knowledge of the functions of SHP2 in IL-6-induced JAK/STAT signalling. SHP2 is not only a repressor of basal and cytokine-induced STAT3 activity, but also ensures robustness and transmission of information. [Image: see text] Plain English summary Cells within a multicellular organism communicate with each other to exchange information about the environment. Communication between cells is facilitated by soluble molecules that transmit information from one cell to the other. Cytokines such as interleukin-6 are important soluble mediators that are secreted when an organism is faced with infections or inflammation. Secreted cytokines bind to receptors within the membrane of their target cells. This binding induces activation of an intracellular cascade of reactions called signal transduction, which leads to cellular responses. An important example of intracellular signal transduction is JAK/STAT signalling. In healthy organisms signalling is controlled and timed by regulatory mechanisms, whose activation results in a controlled shutdown of signalling pathways. Interestingly, not all cells within an organism are identical. They differ in the amount of proteins involved in signal transduction, such as STAT3. These differences shape cellular communication and responses to intracellular signalling. Here, we show that an important negative regulatory protein called SHP2 (or PTPN11) is not only responsible for shutting down signalling, but also for steering signalling in heterogeneous cell populations. SHP2 increases robustness of STAT3 activation against variable STAT3 amounts in individual cells. Additionally, it increases the amount of information transferred through JAK/STAT signalling by increasing the dynamic range of pathway activation in heterogeneous cell populations. This is an amazing new function of negative regulatory proteins that contributes to communication in heterogeneous multicellular organisms in health and disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-021-00770-7. BioMed Central 2021-09-16 /pmc/articles/PMC8444181/ /pubmed/34530865 http://dx.doi.org/10.1186/s12964-021-00770-7 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Fiebelkow, Jessica
Guendel, André
Guendel, Beate
Mehwald, Nora
Jetka, Tomasz
Komorowski, Michal
Waldherr, Steffen
Schaper, Fred
Dittrich, Anna
The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling
title The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling
title_full The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling
title_fullStr The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling
title_full_unstemmed The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling
title_short The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling
title_sort tyrosine phosphatase shp2 increases robustness and information transfer within il-6-induced jak/stat signalling
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444181/
https://www.ncbi.nlm.nih.gov/pubmed/34530865
http://dx.doi.org/10.1186/s12964-021-00770-7
work_keys_str_mv AT fiebelkowjessica thetyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling
AT guendelandre thetyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling
AT guendelbeate thetyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling
AT mehwaldnora thetyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling
AT jetkatomasz thetyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling
AT komorowskimichal thetyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling
AT waldherrsteffen thetyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling
AT schaperfred thetyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling
AT dittrichanna thetyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling
AT fiebelkowjessica tyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling
AT guendelandre tyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling
AT guendelbeate tyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling
AT mehwaldnora tyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling
AT jetkatomasz tyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling
AT komorowskimichal tyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling
AT waldherrsteffen tyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling
AT schaperfred tyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling
AT dittrichanna tyrosinephosphataseshp2increasesrobustnessandinformationtransferwithinil6inducedjakstatsignalling