An integrative proteotranscriptomics approach reveals new ADAM9 substrates and downstream pathways.
Biorxiv : the Preprint Server for Biology
|November 22, 2024
Summary
We developed a new proteotranscriptomics method to identify targets of membrane protein shedding enzymes called sheddases. This approach revealed ADAM9 sheddase substrates and downstream signaling pathways involved in diseases like cancer and COVID-19.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Membrane protein shedding regulates cell signaling and adhesion.
- Dysregulated shedding is linked to various diseases.
- Identifying sheddase substrates and downstream targets is challenging with current methods like secretomics.
Purpose of the Study:
- To develop and apply an integrative proteotranscriptomics approach to identify transcriptional and post-transcriptional targets of the sheddase ADAM9.
- To uncover signaling pathways regulated by ADAM9.
- To identify direct and indirect substrates of ADAM9, including those missed by secretomics.
Main Methods:
- Developed an integrative proteotranscriptomics approach.
- Applied the method to study the disintegrin metalloproteinase ADAM9.
- Analyzed transcriptional and post-transcriptional changes downstream of ADAM9 activity.
Main Results:
- Identified signaling pathways regulated by ADAM9, including mTOR and FOXO pathways.
- Discovered several direct and indirect substrates of ADAM9.
- Found that some ADAM9 substrates are not easily detected by secretomics.
Conclusions:
- The integrative proteotranscriptomics approach is effective for identifying sheddase substrates and downstream targets.
- ADAM9 plays a role in disease pathophysiology through its identified substrates and regulated pathways.
- This method can be broadly applied to study other sheddases.
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