Mitochondria are signaling organelles implicated in cancer, but the mechanisms are elusive. Here, we show that Parkin, an E3 ubiquitination (Ub) ligase altered in Parkinson's disease, forms a complex with the regulator of cell motility, Kindlin-2 (K2), at mitochondria of tumor cells. In turn, Parkin ubiquitinates Lys581 and Lys582 using Lys48 linkages, resulting in proteasomal degradation of K2 and shortened half-life from ∼5 h to ∼1.5 h. Loss of K2 inhibits focal adhesion turnover and β1 integrin activation, impairs membrane lamellipodia size and frequency, and inhibits mitochondrial dynamics, altogether suppressing tumor cell-extracellular matrix interactions, migration, and invasion. Conversely, Parkin does not affect tumor cell proliferation, cell cycle transitions, or apoptosis. Expression of a Parkin Ub-resistant K2 Lys581Ala/Lys582Ala double mutant is sufficient to restore membrane lamellipodia dynamics, correct mitochondrial fusion/fission, and preserve single-cell migration and invasion. In a 3D model of mammary gland developmental morphogenesis, impaired K2 Ub drives multiple oncogenic traits of EMT, increased cell proliferation, reduced apoptosis, and disrupted basal-apical polarity. Therefore, deregulated K2 is a potent oncogene, and its Ub by Parkin enables mitochondria-associated metastasis suppression.
Yeon, Minjeong; Bertolini, Irene; Agarwal, Ekta; Ghosh, Jagadish C; Tang, Hsin-Yao; Speicher, David W.; Keeney, Frederick; Sossey-Alaoui, Khalid; Pluskota, Elzbieta; Bialkowska, Katarzyna; Plow, Edward F.; Languino, Lucia R.; Skordalakes, Emmanuel; Caino, M Cecilia; and Altieri, Dario C., "Parkin Ubiquitination of Kindlin-2 Enables Mitochondria-Associated Metastasis Suppression" (2023). Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers. Paper 2.
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