Ledet Russell J, Ruff Sophie E, Wang Yu, Nayak Shruti, Schneider Jeffrey A, Ueberheide Beatrix, Logan Susan K, Garabedian Michael J
Departments of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
Department of Urology, New York University School of Medicine, New York, NY, 10016, USA.
Commun Biol. 2021 Jan 4;4(1):36. doi: 10.1038/s42003-020-01528-6.
PIM1 is a serine/threonine kinase that promotes and maintains prostate tumorigenesis. While PIM1 protein levels are elevated in prostate cancer relative to local disease, the mechanisms by which PIM1 contributes to oncogenesis have not been fully elucidated. Here, we performed a direct, unbiased chemical genetic screen to identify PIM1 substrates in prostate cancer cells. The PIM1 substrates we identified were involved in a variety of oncogenic processes, and included N-Myc Downstream-Regulated Gene 1 (NDRG1), which has reported roles in suppressing cancer cell invasion and metastasis. NDRG1 is phosphorylated by PIM1 at serine 330 (pS330), and the level of NDRG1 pS330 is associated higher grade prostate tumors. We have shown that PIM1 phosphorylation of NDRG1 at S330 reduced its stability, nuclear localization, and interaction with AR, resulting in enhanced cell migration and invasion.
PIM1是一种丝氨酸/苏氨酸激酶，可促进和维持前列腺肿瘤发生。虽然与局部疾病相比，前列腺癌中PIM1蛋白水平升高，但PIM1促成肿瘤发生的机制尚未完全阐明。在此，我们进行了一项直接、无偏差的化学遗传学筛选，以鉴定前列腺癌细胞中的PIM1底物。我们鉴定出的PIM1底物参与了多种致癌过程，包括N- Myc下游调控基因1（NDRG1），该基因在抑制癌细胞侵袭和转移方面具有报道的作用。NDRG1在丝氨酸330（pS330）处被PIM1磷酸化，NDRG1 pS330的水平与更高分级的前列腺肿瘤相关。我们已经表明，PIM1在S330处对NDRG1的磷酸化降低了其稳定性、核定位以及与雄激素受体（AR）的相互作用，导致细胞迁移和侵袭增强。
