An integrin α3β1-CSTF3 signaling axis regulates alternative polyadenylation of Mmp9 mRNA

The laminin-binding integrin α3β1 is highly expressed in epidermal keratinocytes, where it coordinates diverse cellular functions and gene expression during skin remodeling. Here, we show that α3β1-MEK/ERK signaling operates in vivo to promote proximal polyadenylation site (PAS) usage in the Mmp9 gene, generating a short, more stable mRNA transcript. Using mice with inducible, epidermis-specific α3 deletion, RNA in situ hybridization revealed that loss of α3β1 increased the long Mmp9 transcript in healing wounds and epidermal tumors. α3β1-MEK/ERK signaling in keratinocytes induced the expression of the cleavage stimulation factor CSTF3, a known regulator of alternative polyadenylation (APA), while CSTF3 knockdown shifted Mmp9 toward distal PAS usage. Moreover, α3 deletion reduced Cstf3 gene expression and altered APA in vivo. Genome-wide DaPars2 analysis identified α3β1-dependent APA across numerous genes, including some encoding components of the keratinocyte secretome. Together, these findings define a novel α3β1-MEK/ERK-CSTF3 axis that orchestrates post-transcriptional gene regulation through APA, revealing α3β1 as a potential target for wound and cancer therapies.