An Integrative Proteotranscriptomics Approach Reveals New ADAM9 Substrates and Downstream Pathways

Area of Science:

• Biochemistry
• Molecular Biology
• Proteomics

Background:

• ADAM9 is a cell-surface metalloprotease involved in ectodomain shedding.
• Dysregulated ADAM9 activity is linked to diseases including cancer, autoimmunity, and COVID-19.
• Understanding ADAM9 substrates is crucial for elucidating its roles in health and disease.

Purpose of the Study:

• To systematically identify transcriptional and post-transcriptional targets of ADAM9.
• To uncover signaling pathways regulated by ADAM9.
• To identify direct and indirect substrates of ADAM9.

Main Methods:

• Integrative proteotranscriptomics approach.
• Utilized HCT116 cells with a stable diploid karyotype for omics analyses.
• Systematic identification of ADAM9 targets.

Main Results:

• Identified major signaling pathways downstream of ADAM9, including the mTOR and FOXO pathways.
• Uncovered direct and indirect substrates of ADAM9.
• Provided mechanistic insights into ADAM9 function.

Conclusions:

• ADAM9 regulates key oncogenic (mTOR) and tumor suppressor (FOXO) pathways.
• Identified novel substrates mediating ADAM9's pathophysiological roles.
• Developed a transferable method for studying membrane proteases.