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

doi:10.1016/j.isci.2022.105419

B cell linker protein (BLNK) is a regulator of Met receptor signaling and trafficking in non-small cell lung cancer

iScience. 2022 Oct 20;25(11):105419. doi: 10.1016/j.isci.2022.105419. eCollection 2022 Nov 18.

Authors

Shivanthy Pathmanathan^{1

2}, Zhong Yao^{1

3}, Paula Coelho^{4

5}, Robert Valla^{1

6}, Luka Drecun^{1

2}, Caroline Benz^{1

7}, Jamie Snider^{1

3}, Punit Saraon¹, Ingrid Grozavu^{1

3}, Max Kotlyar⁸, Igor Jurisica^{8

9

10}, Morag Park^{4

5

11

12}, Igor Stagljar^{1

2

3

13

14}

Affiliations

¹ Donnelly Centre, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada.
² Department of Molecular Genetics, Temerty Faculty of Medicine, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada.
³ Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, 160 College St, Room 1204, Toronto, ON M5S 3E1, Canada.
⁴ Department of Biochemistry, McGill University, Montreal, QC, Canada.
⁵ Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC, Canada.
⁶ Department of Molecular Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia.
⁷ Department of Chemistry - University of Konstanz, Universitätsstrasse 10, 78464 Konstanz, Germany.
⁸ 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.
⁹ Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, ON, Canada.
¹⁰ Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia.
¹¹ Department of Medicine, McGill University, Montreal, QC, Canada.
¹² Department of Oncology, McGill University, Montreal, QC, Canada.
¹³ Mediterranean Institute for Life Sciences, Split, Croatia.
¹⁴ School of Medicine, University of Split, Split, Croatia.

Abstract

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.

Keywords: Cancer systems biology; Cell biology.