puc-header

Analysis of the Human Kinome and Phosphatome Reveals Diseased Signaling Networks Induced by Overexpression

50 Pages Posted: 6 Jun 2018 Sneak Peek Status: Review Complete

See all articles by Xiao-Kang Lun

Xiao-Kang Lun

University of Zurich - Institute of Molecular Life Sciences; University of Zurich - Molecular Life Science Ph.D. Program

Damian Szklarczyk

University of Zurich - Institute of Molecular Life Sciences

Attila Gábor

RWTH Aachen University - Joint Research Center for Computational Biomedicine

Nadine Dobberstein

University of Zurich - Institute of Molecular Life Sciences

Vito RT Zanotelli

University of Zurich - Institute of Molecular Life Sciences; University of Zurich - Systems Biology Ph.D. Program

Julio Saez-Rodriguez

European Bioinformatics Institute; RWTH Aachen University - Joint Research Center for Computational Biomedicine

Christian von Mering

University of Zurich - Institute of Molecular Life Sciences

Bernd Bodenmiller

University of Zurich - Institute of Molecular Life Sciences

More...

Abstract

Kinase and phosphatase overexpression drives tumorigenesis and drug resistance in many cancer types. Signaling networks reprogrammed by protein overexpression remain largely uncharacterized, hindering discovery of paths to therapeutic intervention. We previously developed a single cell proteomics approach based on mass cytometry that enables quantitative assessment of overexpression effects on the signaling network. Here we applied this approach in a human kinome- and phosphatome-wide study to assess how 649 individually overexpressed proteins modulate the cancer-related signaling network in HEK293T cells. Based on these data we expanded the functional classification of human kinases and phosphatases and detected 208 novel signaling relationships. In the signaling dynamics analysis, we showed that increased ERKspecific phosphatases sustained proliferative signaling, and using a novel combinatorial overexpression approach, we confirmed this phosphatasedriven mechanism of cancer progression. Finally, we identified 54 proteins that caused ligand-independent ERK activation with potential as biomarkers for drug resistance in cells carrying BRAF mutations.

Suggested Citation

Lun, Xiao-Kang and Szklarczyk, Damian and Gábor, Attila and Dobberstein, Nadine and Zanotelli, Vito RT and Saez-Rodriguez, Julio and Mering, Christian von and Bodenmiller, Bernd, Analysis of the Human Kinome and Phosphatome Reveals Diseased Signaling Networks Induced by Overexpression (2018). Available at SSRN: https://ssrn.com/abstract=3188423 or http://dx.doi.org/10.2139/ssrn.3188423
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Xiao-Kang Lun (Contact Author)

University of Zurich - Institute of Molecular Life Sciences

Winterthurerstrasse 190
Zurich, CH-8057
Switzerland

University of Zurich - Molecular Life Science Ph.D. Program

Winterthurerstr. 190
Zurich
Switzerland

Damian Szklarczyk

University of Zurich - Institute of Molecular Life Sciences

Winterthurerstrasse 190
Zurich, CH-8057
Switzerland

Attila Gábor

RWTH Aachen University - Joint Research Center for Computational Biomedicine

Aachen
Germany

Nadine Dobberstein

University of Zurich - Institute of Molecular Life Sciences

Winterthurerstrasse 190
Zurich, CH-8057
Switzerland

Vito RT Zanotelli

University of Zurich - Institute of Molecular Life Sciences

Winterthurerstrasse 190
Zurich, CH-8057
Switzerland

University of Zurich - Systems Biology Ph.D. Program

Zurich
Switzerland

Julio Saez-Rodriguez

European Bioinformatics Institute ( email )

Cambridge
United Kingdom

RWTH Aachen University - Joint Research Center for Computational Biomedicine ( email )

Aachen
Germany

Christian von Mering

University of Zurich - Institute of Molecular Life Sciences

Winterthurerstrasse 190
Zurich, CH-8057
Switzerland

Bernd Bodenmiller

University of Zurich - Institute of Molecular Life Sciences ( email )

Winterthurerstrasse 190
Zurich, CH-8057
Switzerland

Click here to go to Cell.com

Paper statistics

Abstract Views
841
Downloads
53