PARKIN UBIQUITINATION OF KINDLIN-2 ENABLES MITOCHONDRIA-ASSOCIATED METASTASIS SUPPRESSION.

Mitochondria are signaling organelles implicated in cancer, but the mechanisms are elusive. Here, we show that Parkin, an E3 ubiquitin ligase altered in Parkinson's Disease (PD), 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-ECM interactions, migration, and invasion. Conversely, Parkin does not affect tumor cell proliferation, cell cycle transitions or apoptosis. Expression of a Parkin ubiquitination-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 ubiquitination 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 ubiquitination by Parkin enables mitochondria-associated metastasis suppression.