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Abstract Although targeted therapies in prostate cancer have clinically shown successful outcomes, resistance to these therapies and acquisition of lineage plasticity pose challenges for fully treating prostate cancer. Among several microscopic perspectives to solve these obstacles, much evidence has emerged indicating that mitochondria dynamics are closely associated with tumor metastasis and tumor progression in various types of cancer. The E3 ubiquitin ligase Parkin is associated with PINK1-mediated mitophagy, allowing cells to control mitochondria damages and generate the needed energy to survive in harsh physiological conditions. Interestingly, we found that Parkin potentially ubiquitinates proteins independently of PINK1-associated mitophagy. By SALIC analysis, we found that K681 and K582 of Kindlin-2 is one of the potential ubiquitination sites by Parkin in prostate cancer cells. Kindlin-2 is a cytoskeletal membrane protein and is a component of the focal adhesion complex. Computational modeling suggested that N-terminal region of Kindlin-2 binds to Parkin, with K581 and K582 of Kindlin-2 exposed outside for ubiquitination. Our studies showed that Kindlin-2 is ubiquitinated and degraded by wild-type Parkin but not by the catalytic site, C431S, mutant Parkin. Furthermore, K581A and K582A mutant Kindlin-2 did not exhibit poly-ubiquitination under conditions of Parkin overexpression. Surprisingly, in our immunofluorescence study, Kindlin-2 was recruited to the mitochondria and co-localized with Parkin. From a mitochondrial functional perspective, wild-type Kindlin-2 reduced mitochondria dynamics, whereas mutant Kindlin-2 didn’t in the presence of Parkin. This suggests that the cytoskeletal protein Kindlin-2 might play a role in mitochondrial dynamics that mediates tumor metastasis. Wild-type Kindlin-2 reduced both focal adhesion generation and decay, unlike mutant Kindlin-2 under Parkin-induced condition. Additionally, this pattern was observed in the single cell lamellipodia dynamics through live cell imaging. 2D and 3D cell invasive assays supported the evidence that Parkin decreases tumor metastatic potential by ubiquitinating Kindlin-2 and regulating mitochondria and focal adhesion dynamics. Our findings indicate that Parkin reduces tumor metastatic potential by ubiquitinating Kindlin-2 and demonstrate the possibility as a therapeutic agent for advanced and immune suppressive tumors. Furthermore, Parkin could be a promising agent for Parkin suppressed tumor patients in line with personalized cancer therapy development. Citation Format: Minjeong Yeon, Irene Bertolini, Dario C. Altieri. Kindlin-2: a novel target of Parkin regulating cancer metastasis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1276.
Yeon et al. (Fri,) studied this question.