USP8 modulates ubiquitination of LRIG1 for Met degradation.
The Met receptor tyrosine kinase is an attractive target for cancer therapy as it promotes invasive tumor growth. SAIT301 is a novel anti-Met antibody, which induces LRIG1-mediated Met degradation and inhibits tumor growth. However, detailed downstream mechanism by which LRIG1 mediates target protein down-regulation is unknown. In the present study, we discovered that SAIT301 induces ubiquitination of LRIG1, which in turn promotes recruitment of Met and LRIG1 complex to the lysosome through its interaction with Hrs, resulting in concomitant degradation of both LRIG1 and Met. We also identified USP8 as a LRIG1-specific deubiquitinating enzyme, reporting the interaction between USP8 and LRIG1 for the first time. SAIT301 triggers degradation of LRIG1 by inhibiting the interaction of LRIG1 and USP8, which regulates ubiquitin modification and stability of LRIG1. In summary, SAIT301 employs ubiquitination of LRIG1 for its highly effective Met degradation. This unique feature of SAIT301 enables it to function as a fully antagonistic antibody without Met activation. We found that USP8 is involved in deubiquitination of LRIG1, influencing the efficiency of Met degradation. The relation of Met, LRIG1 and USP8 strongly supports the potential clinical benefit of a combination treatment of a USP8 inhibitor and a Met inhibitor, such as SAIT301.
BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, 130 Samsung-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 443-803, Republic of Korea.
Young Mi
YM
Oh
BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, 130 Samsung-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 443-803, Republic of Korea.
Saet Byoul
SB
Lee
BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, 130 Samsung-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 443-803, Republic of Korea.
Jaehyun
J
Choi
BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, 130 Samsung-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 443-803, Republic of Korea.
Hye-Young
HY
Suh
BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, 130 Samsung-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 443-803, Republic of Korea.
Seonhui
S
Shim
BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, 130 Samsung-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 443-803, Republic of Korea.
Yun-Jeong
YJ
Song
BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, 130 Samsung-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 443-803, Republic of Korea.
Bogyou
B
Kim
BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, 130 Samsung-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 443-803, Republic of Korea.
Ji Min
JM
Lee
BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, 130 Samsung-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 443-803, Republic of Korea.
Seung Ja
SJ
Oh
BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, 130 Samsung-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 443-803, Republic of Korea.
Yunju
Y
Jeong
BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, 130 Samsung-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 443-803, Republic of Korea.
Kwang Ho
KH
Cheong
BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, 130 Samsung-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 443-803, Republic of Korea.
Paul H
PH
Song
BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, 130 Samsung-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, 443-803, Republic of Korea.
Kyung-Ah
KA
Kim
D045744:Cell Line, Tumor; D010450:Endopeptidases / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D059748:Proteolysis; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
D056827:Endosomal Sorting Complexes Required for Transport; C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D010450:Endopeptidases; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase