bims-hypusi 2024-10-13 papers

Issue of 2024–10–13
two papers selected by
Sebastian J. Hofer, University of Graz

Cell Rep. 2024 Oct 09. pii: S2211-1247(24)01182-3. [Epub ahead of print]43(10): 114831

ERK1/2 interaction with DHPS regulates eIF5A deoxyhypusination independently of ERK kinase activity.

Andrew E Becker, Paweł Kochanowski, Pui-Kei Wu, Elżbieta Wątor, Wenjing Chen, Koushik Guchhait, Artur P Biela, Przemysław Grudnik, Jong-In Park.

This study explores a non-kinase effect of extracellular regulated kinases 1/2 (ERK1/2) on the interaction between deoxyhypusine synthase (DHPS) and its substrate, eukaryotic translation initiation factor 5A (eIF5A). We report that Raf/MEK/ERK activation decreases the DHPS-ERK1/2 interaction while increasing DHPS-eIF5A association in cells. We determined the cryoelectron microscopy (cryo-EM) structure of the DHPS-ERK2 complex at 3.5 Å to show that ERK2 hinders substrate entrance to the DHPS active site, subsequently inhibiting deoxyhypusination in vitro. In cells, impairing the ERK2 activation loop, but not the catalytic site, prolongs the DHPS-ERK2 interaction irrespective of Raf/MEK signaling. The ERK2 Ser-Pro-Ser motif, but not the common docking or F-site recognition sites, also regulates this complex. These data suggest that ERK1/2 dynamically regulate the DHPS-eIF5A interaction in response to Raf/MEK activity, regardless of its kinase function. In contrast, ERK1/2 kinase activity is necessary to regulate the expression of DHPS and eIF5A. These findings highlight an ERK1/2-mediated dual kinase-dependent and -independent regulation of deoxyhypusination.

Keywords: CP: Molecular biology; MAP kinase; Raf/MEK/ERK pathway; cryo-EM; cryogenic electron microscopy; deoxyhypusine synthase; eukaryotic translation initiation factor 5A; extracellular-signal-regulated kinase 1/2; hypusination; hypusine; non-kinase effect

DOI: https://doi.org/10.1016/j.celrep.2024.114831

Pharmacol Res. 2024 Oct 09. pii: S1043-6618(24)00398-0. [Epub ahead of print] 107453

Novel deoxyhypusine synthase (DHPS) inhibitors target hypusination-induced vasculogenic mimicry (VM) against malignant melanoma.

Xi-He Zhao, Jian Ma, Jing-Si Guo, Kai-Li Liu, Yu-Xi Qin, Long-Tian Li, Ji-Fang Zhang, Yue-Ying Yang, Shi-Chen Zhang, Fan-Hao Meng, Lei Liu, Yue-Hui Yang, Xin-Yang Li.

Vasculogenic mimicry (VM) contributes factor to the poor prognosis of malignant melanoma. Developing deoxyhypusine synthase (DHPS) inhibitors against melanoma VM is clinically essential. In this study, we optimized and synthesized a series of compounds based on the candidate structure, and the hit compound 7k was identified through enzyme assay and cell viability inhibition screening. Both inside and outside the cell, 7k's ability to target DHPS and its high affinity were demonstrated. Molecular dynamics and point mutation indicated that mutations of K329 or V129 in DHPS abolish 7k's inhibitory activity. Using PCR arrays, solid-state antibody microarrays, and angiogenesis assays investigated 7k's impact on melanoma cells to reveal that DHPS regulates melanoma VM by promoting FGFR2 and c-KIT expression. Surprisingly, 7k was discovered to inhibit MC1R-mediated melanin synthesis in the zebrafish. Pharmacokinetic evaluations demonstrated 7k's favorable properties, and xenograft models evidenced its notable anti-melanoma efficacy, achieving a TGI of 73%. These results highlighted DHPS as key in melanoma VM formation and confirmed 7k's potential as a novel anti-melanoma agent.

Keywords: DHPS; Melanoma; Vasculogenic mimicry; eIF5A-Hypusine

DOI: https://doi.org/10.1016/j.phrs.2024.107453