Dual Roles of p53‐Related Protein Kinase in Cytoskeletal Remodeling and Translational Control

ABSTRACT P53‐related protein kinase (PRPK; TP53RK) is an evolutionarily conserved atypical kinase whose biology reveals an unexpected integration of translational control, cytoskeletal regulation, and cell‐type‐specific stress responses. As a core component of the TCTC complex ( T hreonyl‐ C arbamoyl T ransferase C omplex), PRPK participates in the universally conserved synthesis of the tRNA modification t 6 A, an essential process for translational fidelity, proteostasis, and cellular viability. Structural and biochemical studies from yeast to humans highlight a deeply conserved ATPase‐driven mechanism in which PRPK undergoes conformational rearrangements to activate the catalytic subunit Tcs3, thereby coordinating tRNA positioning. Beyond this canonical role, PRPK displays additional functions. In Drosophila and mammalian systems, PRPK engages cytoskeletal regulators, including Rab35 and Arp2/3 subunits, to influence actin organization, neuronal polarity, and cell migration. These interactions suggest a second, TCTC‐independent functional module through which PRPK integrates signaling pathways such as AKT and TOPK to shape cell survival, axon specification, and tumor progression. Dysregulation of PRPK in human disease further underscores its pleiotropy, as gain‐of‐function mechanisms promote oncogenesis and metastasis. In contrast, loss‐of‐function mutations in PRPK or other TCTC components cause Galloway–Mowat syndrome, characterized by microcephaly, nephrotic syndrome, and profound defects in proteostasis and cytoskeletal integrity. This Perspective synthesizes emerging concepts of PRPK as a dual‐role regulator, acting in tRNA biology as well as in cytoskeletal and stress responses. We delineate unresolved questions regarding substrate identity, structural regulation, cell‐type specificity, and the feasibility of selectively targeting PRPK for therapeutic purposes. Taken together, these findings reveal the richness and complexity of PRPK functions as a molecular regulator of translation, signaling, and cytoskeletal dynamics that are evolutionarily and mechanistically intertwined. image