Alternative mRNA splicing generates two distinct ADAM12 prodomain variants

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Human ADAM12 (a disintegrin and metalloproteinase domain 12) exists in multiple transcript variants.
• Transcript variant 1 (Var-1b) encodes ADAM12-Lb, containing a species-specific VIL motif, which differs from other human ADAMs.
• The expression and function of a shorter variant, Var-1a encoding ADAM12-La, remain unclear.

Purpose of the Study:

• To investigate the expression and cellular behavior of human ADAM12 transcript variants Var-1a and Var-1b.
• To determine the correct canonical form of transmembrane ADAM12.

Main Methods:

• Analysis of human mammary epithelial and breast cancer cell lines.
• Assessment of transcript expression.
• Evaluation of protein processing and intracellular trafficking pathways.

Main Results:

• Both Var-1a and Var-1b transcripts are expressed in human mammary epithelial and breast cancer cells.
• ADAM12-La undergoes proteolytic cleavage and cell surface trafficking, similar to orthologs in other species.
• ADAM12-Lb is retained within the endoplasmic reticulum and is not proteolytically processed.
• Significant variations in the relative abundance of ADAM12-La and ADAM12-Lb proteins were observed across different breast cancer cell lines.

Conclusions:

• The canonical transmembrane form of human ADAM12 is Var-1a/ADAM12-La.
• Var-1b/ADAM12-Lb, currently prevalent in databases, exhibits aberrant processing and trafficking.
• Differential expression and processing of ADAM12 variants suggest distinct biological roles in breast cancer.