Ras Isoforms from Lab Benches to Lives—What Are We Missing and How Far Are We?

Nair, Arathi; Kubatzky, Katharina F.; Saha, Bhaskar

doi:10.3390/ijms22126508

Cited by 5 publications

(5 citation statements)

References 203 publications

(230 reference statements)

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“…Palmitoylation is a reversible process catalyzed by thioesterase acyl protein thioesterase1 (APT1). The cyclic palmitoylation and depalmitoylation shuttles H-and N-Ras between the PM and subcellular compartments [49] (Figure 4).…”

Section: C-terminal Carboxy-terminal Modifications and Membrane Targe...mentioning

confidence: 99%

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Regulation of Ras-GTPase Signaling and Localization by Post-Translational Modifications

Nair

Saha

2023

Kinases and Phosphatases

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Ras, a GTP-GDP binary switch protein, transduces signals from diverse receptors to regulate various signaling networks. Three Ras genes encode for protein isoforms, namely, Harvey Ras (H-Ras), Kirsten Ras (K-Ras, with two splice variants, K-Ras4A and K-Ras4B), and Neuroblastoma Ras (N-Ras). The isoforms undergo a series of post-translational modifications that enable their membrane attachment and biological activity. The activation of Ras isoforms is tightly regulated, and any dysregulation affects cellular processes, such as cell division, apoptosis, differentiation, cell migration, etc. The Ras gene is highly prone to mutation, and ~30% of cancers carry somatic mutations in Ras, whereas germline mutations clinically manifest as various rasopathies. In addition to regulation by the Guanine nucleotide exchange factors and the GTPase activation proteins, Ras signaling, and localization are also regulated by phosphorylation-dephosphorylation, ubiquitination, nitrosylation, and acetylation. Herein, we review the regulation of Ras signaling and localization by various regulatory enzymes in depth and assess the current status of Ras drug discovery targeting these regulatory enzymes.

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Section: C-terminal Carboxy-terminal Modifications and Membrane Targe...mentioning

confidence: 99%

“…Kinases Phosphatases 2023, 1, FOR PEER REVIEW 7 palmitoylation and depalmitoylation shuttles H-and N-Ras between the PM and subcellular compartments [49] (Figure 4).…”

Section: C-terminal Carboxy-terminal Modifications and Membrane Targe...mentioning

confidence: 99%

Regulation of Ras-GTPase Signaling and Localization by Post-Translational Modifications

Nair

Saha

2023

Kinases and Phosphatases

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“…The progression of signal transduction is contingent upon the optimal concentration of k-Ras protein centered on the membrane of the plasma (PM) [11][12][13]. Normally, this step is antagonized by entropic equilibration to the extensive surface of the endomembrane [10,14].…”

Section: Introductionmentioning

confidence: 99%

DFT and molecular simulation validation of the binding activity of PDEδ inhibitors for repression of oncogenic k-Ras

Majrashi,

Sabt,

Almahli

et al. 2024

PLoS ONE

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The development of effective drugs targeting the K-Ras oncogene product is a significant focus in anticancer drug development. Despite the lack of successful Ras signaling inhibitors, recent research has identified PDEδ, a KRAS transporter, as a potential target for inhibiting the oncogenic KRAS signaling pathway. This study aims to investigate the interactions between eight K-Ras inhibitors (deltarazine, deltaflexin 1 and 2, and its analogues) and PDEδ to understand their binding modes. The research will utilize computational techniques such as density functional theory (DFT) and molecular electrostatic surface potential (MESP), molecular docking, binding site analyses, molecular dynamic (MD) simulations, electronic structure computations, and predictions of the binding free energy. Molecular dynamic simulations (MD) will be used to predict the binding conformations and pharmacophoric features in the active site of PDEδ for the examined structures. The binding free energies determined using the MMPB(GB)SA method will be compared with the observed potency values of the tested compounds. This computational approach aims to enhance understanding of the PDEδ selective mechanism, which could contribute to the development of novel selective inhibitors for K-Ras signaling.

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“…Ras, a 21KDa GTPase was first discovered as a retroviral gene encoding the isoforms-Harvey-Ras (H-Ras), Kirsten-Ras (K-Ras), and Neuroblastoma-Ras (N-Ras) (Nair et al 2021). These Ras isoforms serve as a molecular switch controlling signals from different cell membrane receptors and thereby comprise the core of the oncogenic circuitry.…”

Section: Introductionmentioning

confidence: 99%

CD40 induces selective routing of Ras isoforms to subcellular compartments

Nair

Chakraborty

Saha

2023

J. Cell Commun. Signal.

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Ras GTPases are central to cellular signaling and oncogenesis. The three loci of the Ras gene encode for four protein isoforms namely Harvey-Ras (H-Ras), Kirsten-Ras (K-Ras 4A and 4B), and Neuroblastoma-Ras (N-Ras) which share ~ 80% sequence similarity and used to be considered functionally redundant. The small molecule inhibitors of Ras lack specificity for the isoforms leading to widespread toxicity in Ras-targeted therapeutics. Ras isoforms' tissue-specific expression and selective association with carcinogenesis, embryonic development, and infection suggested their non-redundancy. We show that CD40, an antigen-presenting cell (APC)-expressed immune receptor, induces selective relocation of H-Ras, K-Ras, and N-Ras to the Plasma membrane (PM) lipid rafts, mitochondria, endoplasmic reticulum (ER), but not to the Golgi complex (GC). The two palmitoylated Ras isoforms-H-Ras and N-Ras-have a similar pattern of colocalization into the lipid-rich raft microdomain of the PM at early time points when compared to non-palmitoylated K-Ras (4B) with polylysine residues. CD40-induced trafficking of H-Ras and K-Ras to mitochondria and ER was found to be similar but different from that of N-Ras. Trafficking of all the Ras isoforms to the GC was independent of CD40 stimulation. The receptor-driven trafficking and spatial segregation of H-Ras, K-Ras, and N-Ras imply isoform-specific subcellular signaling platforms for the functional non-redundancy of Ras isoforms.

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Ras Isoforms from Lab Benches to Lives—What Are We Missing and How Far Are We?

Cited by 5 publications

References 203 publications

Regulation of Ras-GTPase Signaling and Localization by Post-Translational Modifications

Regulation of Ras-GTPase Signaling and Localization by Post-Translational Modifications

DFT and molecular simulation validation of the binding activity of PDEδ inhibitors for repression of oncogenic k-Ras

CD40 induces selective routing of Ras isoforms to subcellular compartments

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