LC3C-Mediated Autophagy Selectively Regulates the Met RTK and HGF-Stimulated Migration and Invasion

Emily S Bell; Paula Pinto Coelho; Colin D H Ratcliffe; Charles V Rajadurai; Pascal Peschard; Richard Vaillancourt; Dongmei Zuo; Morag Park

doi:10.1016/j.celrep.2019.11.063

LC3C-Mediated Autophagy Selectively Regulates the Met RTK and HGF-Stimulated Migration and Invasion

Cell Rep. 2019 Dec 17;29(12):4053-4068.e6. doi: 10.1016/j.celrep.2019.11.063.

Authors

Emily S Bell¹, Paula Pinto Coelho¹, Colin D H Ratcliffe¹, Charles V Rajadurai¹, Pascal Peschard², Richard Vaillancourt¹, Dongmei Zuo², Morag Park³

Affiliations

¹ Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
² Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
³ Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Department of Medicine, McGill University, Montreal, QC H3A 1A3, Canada; Department of Oncology, McGill University, Montreal, QC H3A 1A3, Canada. Electronic address: morag.park@mcgill.ca.

PMID: 31851933
DOI: 10.1016/j.celrep.2019.11.063

Abstract

The Met/hepatocyte growth factor (HGF) receptor tyrosine kinase (RTK) is deregulated in many cancers and is a recognized target for cancer therapies. Following HGF stimulation, the signaling output of Met is tightly controlled by receptor internalization and sorting for degradation or recycling. Here, we uncover a role for autophagy in selective degradation of Met and regulation of Met-dependent cell migration and invasion. Met engagement with the autophagic pathway is dependent on complex formation with the mammalian ATG8 family member MAP1LC3C. LC3C deletion abrogates Met entry into the autophagy-dependent degradative pathway, allowing identification of LC3C domains required for rescue. Cancer cells with low LC3C levels show enhanced Met stability, signaling, and cell invasion. These findings provide mechanistic insight into RTK recruitment to autophagosomes and establish distinct roles for ATG8 proteins in this process, supporting that differential expression of ATG8 proteins can shape the functional consequences of autophagy in cancer development and progression.

Keywords: LC3C; MET; RTK; VHL; autophagy; cancer; cell migration; cell signaling; endocytosis; membrane trafficking.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autophagy / genetics
Autophagy / physiology*
Cell Line, Tumor
Cell Movement / drug effects*
Fluorescent Antibody Technique
Hepatocyte Growth Factor / pharmacology*
Humans
Microtubule-Associated Proteins / genetics
Microtubule-Associated Proteins / metabolism*
Models, Biological
Protein Transport / genetics
Protein Transport / physiology
Proto-Oncogene Proteins c-met / metabolism*
Signal Transduction / drug effects

Substances

MAP1LC3C protein, human
Microtubule-Associated Proteins
Hepatocyte Growth Factor
Proto-Oncogene Proteins c-met

Grants and funding

CIHR/Canada