Proteolysis of CD44 at the cell surface controls a downstream protease network

Area of Science:

• Cell biology
• Molecular biology
• Cancer research

Background:

• Cluster of differentiation 44 (CD44) is a key cell surface receptor and hyaluronan binder.
• CD44 undergoes proteolytic processing, releasing an intracellular domain that regulates gene transcription.
• Altered CD44 isoform expression is linked to cancer progression and epithelial-mesenchymal transition (EMT).

Purpose of the Study:

• To identify novel sheddases of CD44.
• To investigate the regulatory interplay between CD44 and matrix metalloproteinases (MMPs).
• To explore the functional significance of CD44-MMP interactions in cancer-related processes.

Main Methods:

• CRISPR/Cas9 gene editing to deplete CD44 and its sheddases (ADAM10, MMP14) in HeLa cells.
• Analysis of transcriptional regulatory loops using gene expression data (GTEx).
• Functional assays assessing cell proliferation, spheroid formation, migration, and adhesion.

Main Results:

• Meprin β is identified as a novel sheddase of CD44.
• A transcriptional regulatory loop involving ADAM10, CD44, MMP14, and MMP2 was discovered.
• This regulatory network is conserved across various human tissues.
• A strong correlation between CD44 and MMP14 was observed, impacting cellular functions.

Conclusions:

• Meprin β contributes to CD44 processing.
• The identified CD44-MMP regulatory loop plays a role in cancer cell behavior.
• Targeting the CD44-MMP axis may offer therapeutic strategies for cancer treatment.