B cell linker protein (BLNK) is a regulator of Met receptor signaling and trafficking in non-small cell lung cancer
Shivanthy Pathmanathan,
Zhong Yao,
Paula Coelho,
Robert Valla,
Luka Drecun,
Caroline Benz,
Jamie Snider,
Punit Saraon,
Ingrid Grozavu,
Max Kotlyar,
Igor Jurisica,
Morag Park,
Igor Stagljar
Affiliations
Shivanthy Pathmanathan
Donnelly Centre, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, Temerty Faculty of Medicine, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada
Zhong Yao
Donnelly Centre, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada; Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada
Paula Coelho
Department of Biochemistry, McGill University, Montreal, QC, Canada; Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC, Canada
Robert Valla
Donnelly Centre, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada; Department of Molecular Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia
Luka Drecun
Donnelly Centre, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, Temerty Faculty of Medicine, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada
Caroline Benz
Donnelly Centre, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada; Department of Chemistry – University of Konstanz, Universitätsstrasse 10, 78464 Konstanz, Germany
Jamie Snider
Donnelly Centre, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada; Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada
Punit Saraon
Donnelly Centre, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada
Ingrid Grozavu
Donnelly Centre, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada; Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada
Max Kotlyar
Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute and Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON, Canada
Igor Jurisica
Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute and Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON, Canada; Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, ON, Canada; Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
Morag Park
Department of Biochemistry, McGill University, Montreal, QC, Canada; Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC, Canada; Department of Medicine, McGill University, Montreal, QC, Canada; Department of Oncology, McGill University, Montreal, QC, Canada
Igor Stagljar
Donnelly Centre, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, Temerty Faculty of Medicine, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada; Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada; Mediterranean Institute for Life Sciences, Split, Croatia; School of Medicine, University of Split, Split, Croatia; Corresponding author
Summary: Met is an oncogene aberrantly activated in multiple cancers. Therefore, to better understand Met biology and its role in disease we applied the Mammalian Membrane Two-Hybrid (MaMTH) to generate a targeted interactome map of its interactions with human SH2/PTB-domain-containing proteins. We identified thirty interaction partners, including sixteen that were previously unreported. Non-small cell lung cancer (NSCLC)-focused functional characterization of a Met-interacting protein, BLNK, revealed that BLNK is a positive regulator of Met signaling, and modulates localization, including ligand-dependent trafficking of Met in NSCLC cell lines. Furthermore, the interaction between Met and GRB2 is increased in the presence of BLNK, and the constitutive interaction between BLNK and GRB2 is increased in the presence of active Met. Tumor phenotypical assays uncovered roles for BLNK in anchorage-independent growth and chemotaxis of NSCLC cell lines. Cumulatively, this study provides a Met-interactome and delineates a role for BLNK in regulating Met biology in NSCLC context.
