Anna-Kathrine Pedersen

Novo Nordisk Foundation

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Co-Authors

Jesper V. Olsen

University of Copenhagen

Chiara Francavilla

Technical University of Denmark

Kristina B. Emdal

University of Copenhagen

Dorte B. Bekker‐Jensen

Novo Nordisk Foundation

Blagoy Blagoev

University of Southern Denmark

Giuseppe Cazzamali

University of Copenhagen

Peter Kresten Nielsen

Novo Nordisk (Denmark)

Brian C. Searle

The Ohio State University Wexner Medical Center

TÅ

Thomas Åskov Pedersen

Novo Nordisk (Denmark)

Gulnahar B. Mortuza

Novo Nordisk Foundation

Cooperative Institutions

University of Copenhagen

Novo Nordisk Foundation

University of Southern Denmark

Novo Nordisk (Denmark)

Alexander Fleming Biomedical Sciences Research Center

Aarhus University

National and Kapodistrian University of Athens

Spanish National Cancer Research Centre

Foundation Center

Copenhagen University Hospital

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UbiSite approach for comprehensive mapping of lysine and N-terminal ubiquitination sites

Nature Structural & Molecular Biology (2018)

Vyacheslav Akimov Inigo Barrio‐Hernandez Sten V. F. Hansen Philip Hallenborg Anna-Kathrine Pedersen

Ubiquitin-conjugating enzyme

Proteolysis

10.1038/s41594-018-0084-y

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Citations (380)

Optimizing Linear Ion-Trap Data-Independent Acquisition toward Single-Cell Proteomics

Analytical Chemistry (2023)

Teeradon Phlairaharn Zilu Ye Elena Krismer Anna-Kathrine Pedersen Maik Pietzner

A linear ion trap (LIT) is an affordable, robust mass spectrometer that provides fast scanning speed and high sensitivity, where its primary disadvantage is inferior mass accuracy compared to more commonly used time-of-flight or orbitrap (OT) mass analyzers. Previous efforts to utilize the LIT for low-input proteomics analysis still rely on either built-in OTs for collecting precursor data or OT-based library generation. Here, we demonstrate the potential versatility of the LIT for low-input proteomics as a stand-alone mass analyzer for all mass spectrometry (MS) measurements, including library generation. To test this approach, we first optimized LIT data acquisition methods and performed library-free searches with and without entrapment peptides to evaluate both the detection and quantification accuracy. We then generated matrix-matched calibration curves to estimate the lower limit of quantification using only 10 ng of starting material. While LIT-MS1 measurements provided poor quantitative accuracy, LIT-MS2 measurements were quantitatively accurate down to 0.5 ng on the column. Finally, we optimized a suitable strategy for spectral library generation from low-input material, which we used to analyze single-cell samples by LIT-DIA using LIT-based libraries generated from as few as 40 cells.

Orbitrap

Quadrupole ion trap

10.1021/acs.analchem.3c00842

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Citations (11)

Multilayered proteomics reveals molecular switches dictating ligand-dependent EGFR trafficking

Nature Structural & Molecular Biology (2016)

Chiara Francavilla Moreno Papetti Kristoffer T. G. Rigbolt Anna-Kathrine Pedersen Jón Otti Sigurðsson

10.1038/nsmb.3218

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Citations (106)

Optimizing linear ion trap data independent acquisition towards single cell proteomics

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Teeradon Phlairaharn Zilu Ye Elena Krismer Anna-Kathrine Pedersen Maik Pietzner

A linear ion trap (LIT) is an affordable, robust mass spectrometer that proves fast scanning speed and high sensitivity, where its primary disadvantage is inferior mass accuracy compared to more commonly used time-of-flight (TOF) or orbitrap (OT) mass analyzers. Previous efforts to utilize the LIT for low-input proteomics analysis still rely on either built-in OTs for collecting precursor data or OT-based library generation. Here, we demonstrate the potential versatility of the LIT for low-input proteomics as a stand-alone mass analyzer for all mass spectrometry measurements, including library generation. To test this approach, we first optimized LIT data acquisition methods and performed library-free searches with and without entrapment peptides to evaluate both the detection and quantification accuracy. We then generated matrix-matched calibration curves to estimate the lower limit of quantification using only 10 ng of starting material. While LIT-MS1 measurements provided poor quantitative accuracy, LIT-MS2 measurements were quantitatively accurate down to 0.5 ng on column. Finally, we optimized a suitable strategy for spectral library generation from low-input material, which we used to analyze single-cell samples by LIT-DIA using LIT-based libraries generated from as few as 40 cells.

Orbitrap

Quadrupole ion trap

Trap (plumbing)

10.1101/2023.02.21.529444

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Citations (2)

Novel p38α MAP kinase inhibitors identified from yoctoReactor DNA-encoded small molecule library

MedChemComm (2016)

L. Petersen Peter Blakskjær A. Chaikuad Allan Beck Christensen Judith Dietvorst

A DNA-encoded small-molecule library was prepared using yoctoReactor technology followed by binder trap enrichment to identify selective inhibitors with nanomolar potencies against p38α MAP kinase.

10.1039/c6md00241b

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Citations (76)

Multi-layered proteomics identifies insulin-induced upregulation of the EphA2 receptor via the ERK pathway which is dependent on low IGF1R level

Scientific Reports (2024)

Sarah Hyllekvist Jørgensen Kristina B. Emdal Anna-Kathrine Pedersen Lene Nygaard Axelsen Helene Faustrup Kildegaard

Insulin resistance impairs the cellular insulin response, and often precedes metabolic disorders, like type 2 diabetes, impacting an increasing number of people globally. Understanding the molecular mechanisms in hepatic insulin resistance is essential for early preventive treatments. To elucidate changes in insulin signal transduction associated with hepatocellular resistance, we employed a multi-layered mass spectrometry-based proteomics approach focused on insulin receptor (IR) signaling at the interactome, phosphoproteome, and proteome levels in a long-term hyperinsulinemia-induced insulin-resistant HepG2 cell line with a knockout of the insulin-like growth factor 1 receptor (IGF1R KO). The analysis revealed insulin-stimulated recruitment of the PI3K complex in both insulin-sensitive and -resistant cells. Phosphoproteomics showed attenuated signaling via the metabolic PI3K-AKT pathway but sustained extracellular signal-regulated kinase (ERK) activity in insulin-resistant cells. At the proteome level, the ephrin type-A receptor 2 (EphA2) showed an insulin-induced increase in expression, which occurred through the ERK signaling pathway and was concordantly independent of insulin resistance. Induction of EphA2 by insulin was confirmed in additional cell lines and observed uniquely in cells with high IR-to-IGF1R ratio. The multi-layered proteomics dataset provided insights into insulin signaling, serving as a resource to generate and test hypotheses, leading to an improved understanding of insulin resistance.

IRS2

IRS1

Insulin receptor substrate

10.1038/s41598-024-77817-5

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Citations (0)

Molecular basis of Tousled-Like Kinase 2 activation

Nature Communications (2018)

Gulnahar B. Mortuza Dario Hermida Anna-Kathrine Pedersen Sandra Segura‐Bayona Blanca López‐Méndez

Tousled-like kinases (TLKs) are required for genome stability and normal development in numerous organisms and have been implicated in breast cancer and intellectual disability. In humans, the similar TLK1 and TLK2 interact with each other and TLK activity enhances ASF1 histone binding and is inhibited by the DNA damage response, although the molecular mechanisms of TLK regulation remain unclear. Here we describe the crystal structure of the TLK2 kinase domain. We show that the coiled-coil domains mediate dimerization and are essential for activation through ordered autophosphorylation that promotes higher order oligomers that locally increase TLK2 activity. We show that TLK2 mutations involved in intellectual disability impair kinase activity, and the docking of several small-molecule inhibitors of TLK activity suggest that the crystal structure will be useful for guiding the rationale design of new inhibition strategies. Together our results provide insights into the structure and molecular regulation of the TLKs.

10.1038/s41467-018-04941-y

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Citations (40)

Proteomic investigation of Cbl and Cbl-b in neuroblastoma cell differentiation highlights roles for SHP-2 and CDK16

iScience (2021)

Anna-Kathrine Pedersen Anamarija Pfeiffer Gopal Karemore Vyacheslav Akimov Dorte B. Bekker‐Jensen

Neuroblastoma is a highly heterogeneous embryonal solid tumor of the sympathetic nervous system. As some tumors can be treated to undergo differentiation, investigating this process can guide differentiation-based therapies of neuroblastoma. Here, we studied the role of E3 ubiquitin ligases Cbl and Cbl-b in regulation of long-term signaling responses associated with extracellular signal-regulated kinase phosphorylation and neurite outgrowth, a morphological marker of neuroblastoma cell differentiation. Using quantitative mass spectrometry (MS)-based proteomics, we analyzed how the neuroblastoma cell line proteome, phosphoproteome, and ubiquitylome were affected by Cbl and Cbl-b depletion. To quantitatively assess neurite outgrowth, we developed a high-throughput microscopy assay that was applied in combination with inhibitor studies to pinpoint signaling underlying neurite outgrowth and to functionally validate proteins identified in the MS data sets. Using this combined approach, we identified a role for SHP-2 and CDK16 in Cbl/Cbl-b-dependent regulation of extracellular signal-regulated kinase phosphorylation and neurite outgrowth, highlighting their involvement in neuroblastoma cell differentiation.

Neurite

Proteome

10.1016/j.isci.2021.102321

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Citations (12)

Temporal proteomics of NGF-TrkA signaling identifies an inhibitory role for the E3 ligase Cbl-b in neuroblastoma cell differentiation

Science Signaling (2015)

Kristina B. Emdal Anna-Kathrine Pedersen Dorte B. Bekker‐Jensen Kalliopi P. Tsafou Heiko Horn

Proteomic analysis of neurotrophin signaling identifies an inhibitory E3 ubiquitin ligase.

Neurite

10.1126/scisignal.2005769

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Citations (68)

Additional file 7 of Modeling the early stages of Alzheimer’s disease by administering intracerebroventricular injections of human native Aβ oligomers to rats

Figshare (2022)

Eva Anna Marianne Baerends Katia Soud Jonas Folke Anna-Kathrine Pedersen Simon Henmar

Additional file 7. Table S3: Complete lists of the identified proteins for AD and control brain extracts using quantitative mass spectrometry-based proteomics.

10.6084/m9.figshare.20501873

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Citations (0)