TY - JOUR
T1 - LC3C-Mediated Autophagy Selectively Regulates the Met RTK and HGF-Stimulated Migration and Invasion
AU - Bell, Emily S.
AU - Coelho, Paula Pinto
AU - Ratcliffe, Colin D.H.
AU - Rajadurai, Charles V.
AU - Peschard, Pascal
AU - Vaillancourt, Richard
AU - Zuo, Dongmei
AU - Park, Morag
N1 - Publisher Copyright:
© 2019 The Authors
PY - 2019/12/17
Y1 - 2019/12/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85076353499&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076353499&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2019.11.063
DO - 10.1016/j.celrep.2019.11.063
M3 - Article
C2 - 31851933
AN - SCOPUS:85076353499
SN - 2211-1247
VL - 29
SP - 4053-4068.e6
JO - Cell Reports
JF - Cell Reports
IS - 12
ER -
