LC3C mediates selective autophagy of the MET RTK, inhibiting cancer cell invasion

Abstract

Macroautophagy/autophagy is an evolutionarily conserved degradative process with a central role in maintaining cellular homeostasis under conditions of stress, and recent evidence suggests this may occur in part through direct modification of cell signaling. The MET/HGF receptor tyrosine kinase (RTK) signaling axis is an important mediator of cell motility and invasion in normal cell functions and in cancer. We discovered a role for autophagy in regulating ligand-activated MET signaling and cellular responses. When autophagy is induced by starvation, the HGF-activated and internalized MET RTK is selectively recruited for autophagic degradation through complex formation with the MAP1LC3C autophagy protein. Decreased LC3C expression in cancer results in loss of autophagic degradation of MET and enhanced HGF-stimulated cell invasion implicated in metastatic progression. This emerging role for autophagy in selectively regulating signaling proteins has implications for understanding cellular adaptations to stress and the functions of autophagy at different stages of cancer progression.

Keywords: Autophagy; HGF; invasion; LC3C; MET RTK; cancer; cell migration; signaling; signalophagy.

Figure 1.

Regulation of cell signaling by autophagy. (A) If LC3C is present (left), localization of the HGF-activated MET RTK to an autophagic degradative pathway is enhanced by starvation-induced upregulation of autophagy. In cancers where LC3C expression is suppressed (right), MET is not targeted for autophagic degradation, resulting in increased MET recycling, prolonged signaling, and enhanced HGF-stimulated migration and invasion. MVB, multivesicular body; Av, autophagosome. (B) Increased autophagosome formation is induced in response to diverse cellular stresses, and can promote homeostasis through degradation of cellular components, including damaged organelles and pathogens. Autophagy also selectively degrades proteins recruited through binding to cargo receptors that interact with Atg8-family proteins (green circles), such as LC3C. The selective sequestration and lysosomal degradation of signaling proteins, termed signalophagy, could allow autophagy to participate in stress-responsive selective remodeling of cell signaling. This regulatory function for autophagy could be an important contributor to cellular adaptation to stress.