PMID- 35780836
OWN - NLM
STAT- MEDLINE
DCOM- 20220908
LR  - 20240419
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 298
IP  - 8
DP  - 2022 Aug
TI  - Metalloprotease ADAM9 cleaves ephrin-B ligands and differentially regulates Wnt 
      and mTOR signaling downstream of Akt kinase in colorectal cancer cells.
PG  - 102225
LID - S0021-9258(22)00667-6 [pii]
LID - 10.1016/j.jbc.2022.102225 [doi]
LID - 102225
AB  - Ephrin-B signaling has been implicated in many normal and pathological processes, 
      including neural crest development and tumor metastasis. We showed previously 
      that proteolysis of ephrin-B ligands by the disintegrin metalloprotease ADAM13 is 
      necessary for canonical Wnt signal activation and neural crest induction in 
      Xenopus, but it was unclear if these mechanisms are conserved in mammals. Here, 
      we report that mammalian ADAM9 cleaves ephrin-B1 and ephrin-B2 and can substitute 
      for Xenopus ADAM13 to induce the neural crest. We found that ADAM9 expression is 
      elevated in human colorectal cancer (CRC) tissues and that knockdown (KD) of 
      ADAM9 inhibits the migration and invasion of SW620 and HCT116 CRC cells by 
      reducing the activity of Akt kinase, which is antagonized by ephrin-Bs. Akt is a 
      signaling node that activates multiple downstream pathways, including the Wnt and 
      mTOR pathways, both of which can promote CRC cell migration/invasion. 
      Surprisingly, we also found that KD of ADAM9 downregulates Wnt signaling but has 
      negligible effects on mTOR signaling in SW620 cells; in contrast, mTOR activity 
      is suppressed while Wnt signaling remains unaffected by ADAM9 KD in HCT116 cells. 
      These results suggest that mammalian ADAM9 cleaves ephrin-Bs to derepress Akt and 
      promote CRC migration and invasion; however, the signaling pathways downstream of 
      Akt are differentially regulated by ADAM9 in different CRC cell lines, reflecting 
      the heterogeneity of CRC cells in responding to manipulations of upstream Akt 
      regulators.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Chandrasekera, Pathirennehelage
AU  - Chandrasekera P
AD  - Department of Biological Sciences, University of Delaware, Newark, Delaware, USA.
FAU - Perfetto, Mark
AU  - Perfetto M
AD  - Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; 
      Department of Biology, West Virginia University, Morgantown, West Virginia, USA; 
      Pittsburgh Heart, Lung and Blood Vascular Medicine Institute and Department of 
      Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
FAU - Lu, Congyu
AU  - Lu C
AD  - Department of Biological Sciences, University of Delaware, Newark, Delaware, USA.
FAU - Zhuo, Minghui
AU  - Zhuo M
AD  - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell 
      Biology, School of Life Sciences, Xiamen University, Xiamen, China.
FAU - Bahudhanapati, Harinath
AU  - Bahudhanapati H
AD  - Department of Biology, West Virginia University, Morgantown, West Virginia, USA.
FAU - Li, Jiejing
AU  - Li J
AD  - Department of Biology, West Virginia University, Morgantown, West Virginia, USA; 
      Department of Clinical Laboratory, The Affiliated Hospital of KMUST, Medical 
      School, Kunming University of Science and Technology, Kunming, China.
FAU - Chen, Wei-Chih
AU  - Chen WC
AD  - Department of Biology, West Virginia University, Morgantown, West Virginia, USA.
FAU - Kulkarni, Pallavi
AU  - Kulkarni P
AD  - Department of Biological Sciences, University of Delaware, Newark, Delaware, USA.
FAU - Christian, Laura
AU  - Christian L
AD  - Department of Biology, West Virginia University, Morgantown, West Virginia, USA.
FAU - Liu, Jun
AU  - Liu J
AD  - Department of Biochemistry and Cancer Institute, West Virginia University School 
      of Medicine, Morgantown, West Virginia, USA.
FAU - Yien, Yvette Y
AU  - Yien YY
AD  - Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; 
      Pittsburgh Heart, Lung and Blood Vascular Medicine Institute and Department of 
      Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
FAU - Yu, Chundong
AU  - Yu C
AD  - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell 
      Biology, School of Life Sciences, Xiamen University, Xiamen, China.
FAU - Wei, Shuo
AU  - Wei S
AD  - Department of Biological Sciences, University of Delaware, Newark, Delaware, USA. 
      Electronic address: swei@udel.edu.
LA  - eng
GR  - R01 GM114105/GM/NIGMS NIH HHS/United States
GR  - R01 DE029802/DE/NIDCR NIH HHS/United States
GR  - R35 GM133560/GM/NIGMS NIH HHS/United States
GR  - U54 GM104941/GM/NIGMS NIH HHS/United States
GR  - P20 GM104316/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20220701
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Ephrins)
RN  - 0 (Ligands)
RN  - 0 (Membrane Proteins)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.- (Metalloproteases)
RN  - EC 3.4.24.- (ADAM Proteins)
RN  - EC 3.4.24.- (ADAM9 protein, human)
SB  - IM
MH  - ADAM Proteins/*metabolism
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Movement
MH  - Cell Proliferation
MH  - *Colorectal Neoplasms/pathology
MH  - *Ephrins
MH  - Humans
MH  - Ligands
MH  - Mammals/metabolism
MH  - Membrane Proteins/genetics/metabolism
MH  - Metalloproteases/metabolism
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Wnt Signaling Pathway
PMC - PMC9358476
OTO - NOTNLM
OT  - ADAM
OT  - Akt/PKB
OT  - Wnt signaling
OT  - colorectal cancer
OT  - ephrin
OT  - mTOR
COIS- Conflict of interest The authors declare that they have no conflicts of interest 
      with the contents of this article.
EDAT- 2022/07/06 06:00
MHDA- 2022/09/09 06:00
PMCR- 2022/07/01
CRDT- 2022/07/05 08:43
PHST- 2022/01/24 00:00 [received]
PHST- 2022/06/13 00:00 [revised]
PHST- 2022/06/21 00:00 [accepted]
PHST- 2022/07/06 06:00 [pubmed]
PHST- 2022/09/09 06:00 [medline]
PHST- 2022/07/05 08:43 [entrez]
PHST- 2022/07/01 00:00 [pmc-release]
AID - S0021-9258(22)00667-6 [pii]
AID - 102225 [pii]
AID - 10.1016/j.jbc.2022.102225 [doi]
PST - ppublish
SO  - J Biol Chem. 2022 Aug;298(8):102225. doi: 10.1016/j.jbc.2022.102225. Epub 2022 
      Jul 1.