scholarly journals RAS Nanoclusters Selectively Sort Distinct Lipid Headgroups and Acyl Chains

2021 ◽  
Vol 8 ◽  
Author(s):  
Yong Zhou ◽  
Alemayehu A. Gorfe ◽  
John F. Hancock
Keyword(s):  
Splice Variants ◽  
Small Gtpases ◽  
Ras Signaling ◽  
Ras Proteins ◽  
Macromolecular Assembly ◽  
Oncogenic Mutations ◽  
Constitutively Active Mutants ◽  
Primary Location ◽  
Acyl Chains ◽  
Ras Isoforms

RAS proteins are lipid-anchored small GTPases that switch between the GTP-bound active and GDP-bound inactive states. RAS isoforms, including HRAS, NRAS and splice variants KRAS4A and KRAS4B, are some of the most frequently mutated proteins in cancer. In particular, constitutively active mutants of KRAS comprise ∼80% of all RAS oncogenic mutations and are found in 98% of pancreatic, 45% of colorectal and 31% of lung tumors. Plasma membrane (PM) is the primary location of RAS signaling in biology and pathology. Thus, a better understanding of how RAS proteins localize to and distribute on the PM is critical to better comprehend RAS biology and to develop new strategies to treat RAS pathology. In this review, we discuss recent findings on how RAS proteins sort lipids as they undergo macromolecular assembly on the PM. We also discuss how RAS/lipid nanoclusters serve as signaling platforms for the efficient recruitment of effectors and signal transduction, and how perturbing the PM biophysical properties affect the spatial distribution of RAS isoforms and their functions.

scholarly journals Analysis of RAS protein interactions in living cells reveals a mechanism for pan-RAS depletion by membrane-targeted RAS binders

2020 ◽  
Vol 117 (22) ◽  
pp. 12121-12130
Author(s):  
Yao-Cheng Li ◽  
Nikki K. Lytle ◽  
Seth T. Gammon ◽  
Luke Wang ◽  
Tikvah K. Hayes ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Developmental Disorders ◽  
Degradation Pathway ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Ras Proteins ◽  
Ras Protein ◽  
Protein Levels ◽  
Ras Family ◽  
Ras Isoforms

HRAS, NRAS, and KRAS4A/KRAS4B comprise the RAS family of small GTPases that regulate signaling pathways controlling cell proliferation, differentiation, and survival. RAS pathway abnormalities cause developmental disorders and cancers. We found that KRAS4B colocalizes on the cell membrane with other RAS isoforms and a subset of prenylated small GTPase family members using a live-cell quantitative split luciferase complementation assay. RAS protein coclustering is mainly mediated by membrane association-facilitated interactions (MAFIs). Using the RAS–RBD (CRAF RAS binding domain) interaction as a model system, we showed that MAFI alone is not sufficient to induce RBD-mediated RAS inhibition. Surprisingly, we discovered that high-affinity membrane-targeted RAS binding proteins inhibit RAS activity and deplete RAS proteins through an autophagosome–lysosome-mediated degradation pathway. Our results provide a mechanism for regulating RAS activity and protein levels, a more detailed understanding of which should lead to therapeutic strategies for inhibiting and depleting oncogenic RAS proteins.

scholarly journals RAS variant signalling

2018 ◽  
Vol 46 (5) ◽  
pp. 1325-1332 ◽  
Author(s):  
Stephanie P. Mo ◽  
Judy M. Coulson ◽  
Ian A. Prior
Keyword(s):  
Developmental Disorders ◽  
Cellular Proliferation ◽  
Small Gtpases ◽  
Ras Proteins ◽  
Activating Mutations ◽  
Ras Isoforms

RAS proteins are small GTPases that regulate signalling networks that control cellular proliferation and survival. They are frequently mutated in cancer and a commonly occurring group of developmental disorders called RASopathies. We discuss recent findings describing how RAS isoforms and different activating mutations differentially contribute to normal and disease-associated biology and the mechanisms that have been proposed to underpin this.

scholarly journals Decoding RAS isoform and codon-specific signalling

2014 ◽  
Vol 42 (4) ◽  
pp. 742-746 ◽  
Author(s):  
Anna U. Newlaczyl ◽  
Fiona E. Hood ◽  
Judy M. Coulson ◽  
Ian A. Prior
Keyword(s):  
Present Article ◽  
Ras Proteins ◽  
Oncogenic Mutations ◽  
Underlying Mechanisms ◽  
Ras Isoforms

RAS proteins are key signalling hubs that are oncogenically mutated in 30% of all cancer cases. Three genes encode almost identical isoforms that are ubiquitously expressed, but are not functionally redundant. The network responses associated with each isoform and individual oncogenic mutations remain to be fully characterized. In the present article, we review recent data defining the differences between the RAS isoforms and their most commonly mutated codons and discuss the underlying mechanisms.

scholarly journals Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma

2021 ◽  
Author(s):  
Yandan Yang ◽  
Thomas Oellerich ◽  
Ping Chen ◽  
Arnold Bolomsky ◽  
Michele Ceribelli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Amino Acid ◽  
Plasma Cells ◽  
Ras Signaling ◽  
Ras Pathway ◽  
Signaling Complex ◽  
Oncogenic Ras ◽  
Oncogenic Mutations ◽  
Amino Acid Sensing ◽  
Ras Isoforms

Oncogenic mutations within the RAS pathway are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in this disease remain enigmatic and difficult to inhibit therapeutically. We employed an unbiased proteogenomic approach to dissect RAS signaling in MM by combining genome-wide CRISPR-Cas9 screening with quantitative mass spectrometry focused on RAS biology. We discovered that mutant isoforms of RAS organized a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activated mTORC1 by co-opting amino acid sensing pathways. MM tumors with high expression of mTORC1-dependent genes were more aggressive and enriched in RAS mutations, and we detected interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Inhibition of RAS-dependent mTORC1 activity synergized with MEK and ERK inhibitors to quench pathogenic RAS signaling in MM cells. This study redefines the RAS pathway in MM and provides a mechanistic and rational basis to target this novel mode of RAS signaling.

scholarly journals Hydrogen Peroxide Toxicity Induces Ras Signaling in Human Neuroblastoma SH-SY5Y Cultured Cells

2010 ◽  
Vol 2010 ◽  
pp. 1-4 ◽  
Author(s):  
Jirapa Chetsawang ◽  
Piyarat Govitrapong ◽  
Banthit Chetsawang
Keyword(s):  
Hydrogen Peroxide ◽  
Cell Viability ◽  
Cultured Cells ◽  
Neuronal Cells ◽  
Competitive Inhibitor ◽  
Ras Signaling ◽  
Ras Proteins ◽  
Human Neuroblastoma ◽  
Dependent Signaling Pathway

It has been reported that overproduction of reactive oxygen species occurs after brain injury and mediates neuronal cells degeneration. In the present study, we examined the role of Ras signaling on hydrogen peroxide-induced neuronal cells degeneration in dopaminergic neuroblastoma SH-SY5Y cells. Hydrogen peroxide significantly reduced cell viability in SH-SY5Y cultured cells. An inhibitor of the enzyme that catalyzes the farnesylation of Ras proteins, FTI-277, and a competitive inhibitor of GTP-binding proteins, GDP-beta-S significantly decreased hydrogen peroxide-induced reduction in cell viability in SH-SY5Y cultured cells. The results of this study might indicate that a Ras-dependent signaling pathway plays a role in hydrogen peroxide-induced toxicity in neuronal cells.

scholarly journals SmgGDS: An Emerging Master Regulator of Prenylation and Trafficking by Small GTPases in the Ras and Rho Families

2021 ◽  
Vol 8 ◽  
Author(s):  
Anthony C. Brandt ◽  
Olivia J. Koehn ◽  
Carol L. Williams
Keyword(s):  
Splice Variants ◽  
Therapeutic Strategies ◽  
Small Gtpases ◽  
Peptide Inhibitors ◽  
Signaling Cascades ◽  
Therapeutic Targeting ◽  
Growing Body ◽  
History Of ◽  
Rho Family ◽  
Mutant Forms

Newly synthesized small GTPases in the Ras and Rho families are prenylated by cytosolic prenyltransferases and then escorted by chaperones to membranes, the nucleus, and other sites where the GTPases participate in a variety of signaling cascades. Understanding how prenylation and trafficking are regulated will help define new therapeutic strategies for cancer and other disorders involving abnormal signaling by these small GTPases. A growing body of evidence indicates that splice variants of SmgGDS (gene name RAP1GDS1) are major regulators of the prenylation, post-prenylation processing, and trafficking of Ras and Rho family members. SmgGDS-607 binds pre-prenylated small GTPases, while SmgGDS-558 binds prenylated small GTPases. This review discusses the history of SmgGDS research and explains our current understanding of how SmgGDS splice variants regulate the prenylation and trafficking of small GTPases. We discuss recent evidence that mutant forms of RabL3 and Rab22a control the release of small GTPases from SmgGDS, and review the inhibitory actions of DiRas1, which competitively blocks the binding of other small GTPases to SmgGDS. We conclude with a discussion of current strategies for therapeutic targeting of SmgGDS in cancer involving splice-switching oligonucleotides and peptide inhibitors.

Ras proteins as therapeutic targets

2018 ◽  
Vol 46 (5) ◽  
pp. 1303-1311 ◽  
Author(s):  
Atanu Chakraborty ◽  
Emily Linnane ◽  
Sarah Ross
Keyword(s):  
Therapeutic Strategies ◽  
Targeted Therapeutics ◽  
Ras Proteins ◽  
Ras Genes ◽  
Small Molecule Drug ◽  
Oncogenic Mutations ◽  
Recent Developments ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic ◽  
Made In

Oncogenic mutations in RAS genes underlie the pathogenesis of many human tumours, and there has been intense effort for over 30 years to develop effective and tolerated targeted therapeutics for patients with Ras-driven cancers. This review summarises the progress made in Ras drug discovery, highlighting some of the recent developments in directly targeting Ras through advances in small molecule drug design and novel therapeutic strategies.

scholarly journals Drugging an undruggable pocket on KRAS

2019 ◽  
Vol 116 (32) ◽  
pp. 15823-15829 ◽  
Author(s):  
Dirk Kessler ◽  
Michael Gmachl ◽  
Andreas Mantoulidis ◽  
Laetitia J. Martin ◽  
Andreas Zoephel ◽  
...  
Keyword(s):  
Molecular Switches ◽  
Small Gtpases ◽  
Ras Proteins ◽  
Structure Based Drug Design ◽  
Downstream Signaling ◽  
Activating Mutations ◽  
Ras Genes ◽  
Mutant Cells ◽  
Drug Discovery Target ◽  
Micromolar Range

The 3 human RAS genes, KRAS, NRAS, and HRAS, encode 4 different RAS proteins which belong to the protein family of small GTPases that function as binary molecular switches involved in cell signaling. Activating mutations in RAS are among the most common oncogenic drivers in human cancers, with KRAS being the most frequently mutated oncogene. Although KRAS is an excellent drug discovery target for many cancers, and despite decades of research, no therapeutic agent directly targeting RAS has been clinically approved. Using structure-based drug design, we have discovered BI-2852 (1), a KRAS inhibitor that binds with nanomolar affinity to a pocket, thus far perceived to be “undruggable,” between switch I and II on RAS; 1 is mechanistically distinct from covalent KRASG12C inhibitors because it binds to a different pocket present in both the active and inactive forms of KRAS. In doing so, it blocks all GEF, GAP, and effector interactions with KRAS, leading to inhibition of downstream signaling and an antiproliferative effect in the low micromolar range in KRAS mutant cells. These findings clearly demonstrate that this so-called switch I/II pocket is indeed druggable and provide the scientific community with a chemical probe that simultaneously targets the active and inactive forms of KRAS.

scholarly journals Oncogenic KRAS Drives Metabolic Vulnerabilities by Directly Regulating Metabolic Enzymes in Cancer

2020 ◽  
Vol 07 (01) ◽  
pp. 001-002
Author(s):  
Liyi Zhang
Keyword(s):  
Cancer Cells ◽  
Splice Variants ◽  
Human Cancer ◽  
Aerobic Glycolysis ◽  
Metabolic Enzymes ◽  
Glycolytic Enzyme ◽  
Metabolic Reprogramming ◽  
Functional Differences ◽  
Oncogenic Mutations ◽  
Novel Therapeutic Strategies

AbstractMetabolic reprogramming, such as enhanced aerobic glycolysis, allows cancer cells to maintain viability and promote proliferation. It is one of the major consequences of oncogenic mutations. KRAS is the most frequently mutated oncogene in human cancer. It is thought to be closely related to metabolic reprogramming. However, it is not clear whether it can participate in metabolic reprogramming by directly regulating metabolic enzymes. Additionally, the functional differences among the splice variants of KRAS have not been determined. In a study, recently published in Nature, Amendola et al reported a unique interaction between one of the KRAS splice variants (KRAS4A) and the major glycolytic enzyme (hexokinase 1) in cancer cells. Their findings indicated that a better understanding on the regulation of hexokinase 1 by KRAS may reveal novel therapeutic strategies.

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