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Parkin ubiquitination of Kindlin-2 enables mitochondria-associated metastasis suppression.

Authors :
Yeon M
Bertolini I
Agarwal E
Ghosh JC
Tang HY
Speicher DW
Keeney F
Sossey-Alaoui K
Pluskota E
Bialkowska K
Plow EF
Languino LR
Skordalakes E
Caino MC
Altieri DC
Source :
The Journal of biological chemistry [J Biol Chem] 2023 Jun; Vol. 299 (6), pp. 104774. Date of Electronic Publication: 2023 May 02.
Publication Year :
2023

Abstract

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.<br />Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.<br /> (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1083-351X
Volume :
299
Issue :
6
Database :
MEDLINE
Journal :
The Journal of biological chemistry
Publication Type :
Academic Journal
Accession number :
37142218
Full Text :
https://doi.org/10.1016/j.jbc.2023.104774