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

• Published in: Cell reports (Cambridge) Vol. 29; no. 12; pp. 4053 - 4068.e6
• Main Authors: Bell, Emily S., Coelho, Paula Pinto, Ratcliffe, Colin D.H., Rajadurai, Charles V., Peschard, Pascal, Vaillancourt, Richard, Zuo, Dongmei, Park, Morag
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.12.2019; Elsevier
• Subjects: autophagy; cancer; cell migration; cell signaling; endocytosis; LC3C; membrane trafficking; MET; RTK; VHL; autophagy; LC3C; cell signaling; RTK; cell migration; endocytosis; cancer; VHL; MET; membrane trafficking
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.11.063

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. [Display omitted] •Autophagy targets HGF-activated Met for degradation, decreasing Met recycling•Met interaction with MAP1LC3C is required to target Met to autophagosomes•Starvation-induced autophagy decreases Met signaling, cell motility, and invasion•In cancer, VHL loss decreases LC3C and uncouples Met from autophagic regulation The Met RTK regulates migratory invasive responses during development and cancer. Bell et al. describe a mechanism whereby MAP1LC3C selectively targets ligand-activated Met for degradation upon starvation-induced autophagy. Loss of the VHL tumor suppressor decreases LC3C, thereby uncoupling Met from autophagic regulation and enhancing HGF-stimulated invasion in cancer.