Pseudopodium-enriched atypical kinase 1 (PEAK1) in cancer and beyond: a narrative review

Pseudopodium-enriched atypical kinase 1 (PEAK1), initially identified in the pseudopodia of motile cells, is a signaling scaffold and a focal adhesion-linked pseudokinase. Experimental studies link PEAK1 to extracellular matrix sensing, integrin and receptor-mediated signal transduction, cytoskeletal reorganization, epithelial-mesenchymal plasticity, angiogenesis, metastatic progression and responses to therapy. Pro-tumorigenic activities have been described in models of pancreatic, breast, lung, melanoma, anaplastic thyroid and colorectal cancers. However, gastric and colorectal studies indicate that its effects depend on the biological context. Outside of oncology, mechanistic inquiries have characterized PEAK1 in the endothelial GATA2-VEGFR2 signaling pathways and in the maintenance of the intestinal epithelial barrier by protecting ZO-1 from degradation by autophagy. Therefore, instead of being a ubiquitous oncogenic driver, PEAK1 is better characterized as a context dependent regulator that orchestrates signaling networks associated with cell adhesion and growth factors. The following narrative review presents the identification and the molecular features of PEAK1, and summarizes the data concerning its functions in both oncogenic and non-malignant biological contexts. It also explores the upstream regulatory mechanisms, the downstream signaling effectors, the phenotypes related to metastasis and drug resistance, and new therapeutic perspectives. More specifically, the review distinguishes causal functional evidence from expression correlations. It explains which unresolved mechanistic questions must be addressed before clinical translation.