ADAM9: an updated view of its biology and pathology

A disintegrin and metalloprotease 9 (ADAM9) is a catalytically active member of the ADAM family, a group of transmembrane and secreted proteins that regulate adhesion, proteolysis, migration, and cell signaling. ADAM9 exists in two isoforms, ADAM9-L (membrane bound form) and ADAM9-S (secreted form), which differ in structure and have opposing roles in cell migration. Its multiple domains support ectodomain shedding, integrin binding, intracellular signaling, and interactions with SH3-containing proteins. The activity of ADAM9 is regulated at different levels through transcriptional, post-transcriptional, and post-translational mechanisms. ADAM9 cleaves substrates, including pro-HB-EGF, amyloid precursor protein (APP), and MICA, and modulates signaling pathways such as the mTOR, EGFR/AKT, NF-κB, STAT3, and KRAS pathways. ADAM9 dysregulation leads to tumor proliferation, invasion, angiogenesis, immune evasion, and therapy resistance across multiple cancers. In addition to its role in cancers, ADAM9 is implicated in various diseases, including cancer, neurodegenerative, vascular, and inflammatory diseases. Genetic variations and mutations affecting post-translational modification sites highlight their clinical significance. This review summarizes the current knowledge on ADAM9 structure, isoforms, regulatory mechanisms, disease associations, genetic variations, and emerging therapeutic strategies, highlighting its potential as a biomarker and clinically actionable therapeutic target.