Phosphorylation beyond the plasma membrane: How secretory pathway kinases sculpt the cellular dialogue in cancer...

Intercellular communication is critical for tissue homeostasis, development and immune responses, with its disruption often implicated in various diseases, particularly cancer. Secretory pathway kinases and kinase‑like proteins (SPKKPs) constitute a distinctive enzyme class operating within the luminal secretory pathway or extracellular space, positioning them as pivotal regulators of cellular communication. This review consolidates current insights into the role of SPKKPs, including the FAM20 family, four‑jointed box kinase 1 (FJX1) and others, in orchestrating intercellular interactions through the phosphorylation of secreted proteins, extracellular matrix components and extracellular vesicle (EV) cargo. The molecular mechanisms by which SPKKPs modulate key oncogenic signaling pathways, such as PI3K/AKT, ERK/MAPK and SMAD family member 2, across diverse cancer types are examined. Additionally, their involvement in EV‑mediated signaling, extracellular matrix remodeling and regulation of fundamental biological processes, including development, tissue homeostasis and immune coordination, is explored. The review further addresses SPKKP dysregulation in a range of pathologies, from nervous system tumors to gastrointestinal and reproductive cancers, and discusses emerging therapeutic strategies. These strategies include specific kinase inhibitors, FJX1‑targeted peptide vaccines and innovative approaches targeting exosomes carrying SPKKPs substrates. Ultimately, this work highlights the essential role of SPKKPs in intercellular communication networks and their promising potential as diagnostic biomarkers and therapeutic targets, particularly in cancer.