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An Integrative Proteotranscriptomics Approach Reveals New ADAM9 Substrates and Downstream Pathways
Congyu Lu1, Xiaolu Xu2, Neha Sindhu1
1Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; Center for Bioinformatics and Computational Biology, University of Delaware, Newark, Delaware, USA.
Abstract:
A Disintegrin And Metalloproteinase 9 (ADAM9) is a cell-surface protease that can shed the ectodomain of membrane protein substrates. Dysregulated ADAM9 activity has been implicated in several diseases, such as solid tumors, autoimmunity, inflammatory diseases, and coronavirus disease 2019. Despite its importance, the substrates and targets of ADAM9 in normal and pathological processes are poorly understood. Here, we developed an integrative proteotranscriptomics approach to systematically identify the transcriptional and post-transcriptional targets of ADAM9 in HCT116 cells, which have a stable diploid karyotype suitable for omics analyses. Using this approach, we uncovered major signaling pathways downstream of ADAM9, including the oncogenic mechanistic target of rapamycin pathway and the tumor suppressor Forkhead Box O pathway. We also identified several direct and indirect substrates for ADAM9, which may mediate the pathophysiological roles of this protease. This study provides new mechanistic insights into the function of ADAM9 as well as a method that can be applied to other membrane proteases.
Insights
This study identifies targets of the metalloprotease ADAM9, revealing its role in key cancer pathways like mTOR and FOXO. This work offers new insights into ADAM9
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.
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