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J Biol Chem 2022 Aug 01;2988:102225. doi: 10.1016/j.jbc.2022.102225.
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Metalloprotease ADAM9 cleaves ephrin-B ligands and differentially regulates Wnt and mTOR signaling downstream of Akt kinase in colorectal cancer cells.

Chandrasekera P , Perfetto M , Lu C , Zhuo M , Bahudhanapati H , Li J , Chen WC , Kulkarni P , Christian L , Liu J , Yien YY , Yu C , Wei S .

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.

PubMed ID: 35780836
Article link: J Biol Chem
Grant support: [+]

Genes referenced: adam13 adam28.2 adam9 calr ephb3 mtor myc ptpa rps6kb1 snai2
GO keywords: ephrin receptor activity [+]
Antibodies: Adam9 Ab1 Akt1 Ab10 Ctnnb1 Ab21 Ctnnb1 Ab22 HA Ab30 Myc Ab16 Rps6kb1 Ab1 Rps6kb1 Ab2

Disease Ontology terms: colorectal cancer

Article Images: [+] show captions
References [+] :
Ahmed, Epigenetic and genetic features of 24 colon cancer cell lines. 2013, Pubmed