Teemu Haikarainen
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Articles (10)
Year:
2025
Janus kinase 2 (JAK2) mediates type I/II cytokine receptor signaling, but JAK2 is also activated by somatic mutations that cause hematological malignancies by mechanisms that are still incompletely understood. Quantitative superresolution microscopy (qSMLM) showed that erythropoietin receptor (EpoR) exists as monomers and dimerizes upon Epo stimulation or through the predominant JAK2 pseudokinase domain mutations (V617F, K539L, and R683S). Crystallographic analysis complemented by kinase activity analysis and atomic-level simulations revealed distinct pseudokinase dimer interfaces and activation mechanisms for the mutants: JAK V617F activity is driven by dimerization, K539L involves both increased receptor dimerization and kinase activity, and R683S prevents autoinhibition and increases catalytic activity and drives JAK2 equilibrium toward activation state through a wild-type dimer interface. Artificial intelligence–guided modeling and simulations revealed that the pseudokinase mutations cause differences in the pathogenic full-length JAK2 dimers, particularly in the FERM-SH2 domains. A detailed molecular understanding of mutation-driven JAK2 hyperactivation may enable novel therapeutic approaches to selectively target pathogenic JAK2 signaling.
Year:
2024
Year:
2024
Year:
2024
Year:
2023
Year:
2023
Year:
2023
Year:
2023
Year:
2022
Year:
2022
Collaborators (51)
Dustin Duncan
Assistant Professor
Brock University
Petra Sipilä
University of Turku
Jadel M. Kratz
Head of Discovery and Partnerships LATAM
-
Iain Greig
University of Aberdeen
Mike Heilemann
Professor
Goethe University Frankfurt
Davide Maria Ferraris
Associate Professor
Università degli Studi del Piemonte Orientale
Kavita Gadar
University of Birmingham
Nathan Merrill
University of Michigan
Giulia Girolimetti
Università del Salento
Jiyoun Lee
Professor
Sungshin Women's University
Timothy O'Meara
Harvard University
Masfique Mehedi
Assistant Professor
North Dakota State University
GOKHAN CILDIR
University of South Australia
Brandon Pressly
Denali Therapeutics
Gracjan Michlewski
Professor
International Institute of Molecular and Cell Biology
Ashleigh Paparella
Lecturer
University of Sydney
Matti Poutanen
professor
-
Alice Vrielink
University of Western Australia
Kayode Ojo
University of Washington
Evripidis Gavathiotis
Professor
Albert Einstein College of Medicine
Van Hung Vuong Le
Københavns Universitet
Juan José Lasarte
Universidad de Navarra
Alexander Agoulnik
Florida International University
Angelo Taglialatela
Columbia University Irving Medical Center
William Kerr
Professor of Microbiology & Immunology
SUNY Upstate Medical University
Isin Cakir
Assistant Professor of Medicine
University of Pittsburgh
Agnidipta Ghosh
Albert Einstein College of Medicine
Ilpo Vattulainen
University of Helsinki
Christian Weber
Chair in Vascular Medicine and Physician-in-Chief
LMU Klinikum
Olli Silvennoinen
University of Tampere
William Bradshaw
University of Oxford
Deirdre Coombe
Professor
Curtin University
Van Chi Thai
University of Western Australia
Andrea Ilari
Istituto di Biologia e Patologia Molecolari Consiglio Nazionale delle Ricerche
David Siderovski
Professor and Chairman
University of North Texas Health Science Center
Jonathan So
Assistant Professor
Laura and Isaac Perlmutter Cancer Center at NYU Langone Health
Kirsikka Musta
Tampere University
Charlene M. Kahler
University of Western Australia
Silvia Buroni
Associate Professor
Università degli Studi di Pavia
Ashley L St. John
-
Megan O'Mara
Professor
University of Queensland
Vivek Sharma
University of Helsinki
Rajkumar Verma
Assistant Professor
University of Connecticut School of Medicine
Ilkka Junttila
University of Tampere
Robert Bradley
Full Professor
Fred Hutchinson Cancer Research Center
Yogesh Gupta
Associate Professor, with Tenure
University of Texas Health Science Center at San Antonio
Thomas Kampourakis
Lecturer
King’s College London
John Bruning
Senior Lecturer
University of Adelaide
William Brent Clayton
Associate Research Professor of Medicine
Indiana University School of Medicine
Jarrod Mousa
Assistant Professor
University of Georgia
Martin St. Maurice
Associate Professor
Marquette University
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