Pathophysiological Roles of Two Intracellular P-Type ATPases: The Cancer-Associated Na+,K+-ATPase α3 Isoform and the Parkinson's Disease-Related ATP13A2.

P-type ATPases constitute a diverse superfamily of ATP-driven transporters essential for ion homeostasis, membrane asymmetry, and organelle function. Among them, the P2-type Na+,K+-ATPase and the P5-type ATP13A2 have recently emerged as key regulators of cancer progression and neurodegeneration, respectively. In this review, we highlight new insights into the pathological roles of the Na+,K+-ATPase α3 isoform (α3NaK) in malignant cells and ATP13A2 in Parkinson's disease (PD). Cancer tissues frequently overexpress α3NaK which is aberrantly localized to intracellular vesicles and undergoes adhesion-dependent intracellular trafficking. Upon cell detachment, α3NaK translocates to the plasma membrane to sustain survival signaling, thereby promoting anoikis resistance and facilitating the persistence of circulating tumor cells (CTCs). Cardiac glycosides selectively inhibit α3NaK at nanomolar concentrations, suppressing cancer cell proliferation through GLUT1 endocytosis, metabolic inhibition, and downregulation of THADA and LAT1, ultimately inducing anoikis in CTCs and reducing metastasis in vivo. Conversely, ATP13A2 is genetically linked to early-onset parkinsonism and regulates lysosomal integrity, polyamine homeostasis, and neuronal resilience. Recent animal studies demonstrate that adult-onset ATP13A2 loss causes progressive nigrostriatal degeneration, while heterozygous deficiency produces distinct age-dependent cognitive and α-synuclein phenotypes. Beyond its established role in polyamine transport, emerging evidence suggests that ATP13A2 can function as an H+,K+-ATPase-like transporter, contributing to proton and cation handling within the endolysosomal system. Together, these findings underscore the broader physiological and pathological significance of intracellular P-type K+-ATPases and highlight α3NaK and ATP13A2 as promising therapeutic targets in cancer metastasis and PD.