AKAP2: a critical cytoskeletal scaffold for triple-negative breast cancer cell growth and metastasis

Abstract

A Kinase Anchoring Proteins (AKAPs) that coordinate spatiotemporal signaling are increasingly implicated in cancer. Mutations and misregulation to AKAPs can facilitate aberrant signaling through amplified or mislocalization of the signaling enzymes anchored by these scaffolds. Accordingly, elevated AKAP2 is associated with triple-negative breast cancer. In addition, the gene expression of this cytoskeleton-localized scaffold is increased in basal-like breast cancer patient samples compared to other subtypes. A combination of biochemical, cellular, and omics approaches show that AKAP2 cytoskeleton and focal adhesion associated scaffolds contribute to the growth and motility of basal-like triple-negative breast cancer. Proximity proteomics identifies AKAP2 as an element of focal adhesions in MDA-MB-231 cells. In addition, AKAP2 is found to be localized to focal adhesions and constrains the signaling of focal adhesion kinase (FAK). As such, gene silencing of AKAP2 not only decreases FAK levels but also attenuates the phosphorylation of the cell motility adapter protein paxillin on Tyr118. Cell-derived xenograft studies in mice establish that AKAP2 is required for triple-negative breast cancer cell growth and metastasis, phenotypes that are linked to FAK action. These findings discover a new role for focal adhesion-associated AKAP2 in triple-negative breast cancer pathology.