Ras GTPases

Ras GTPases are prototypical members of the RAS superfamily and regulate cytosolic signaling pathways involved in gene expression, as well as regulation of cell proliferation, differentiation and survival. In humans there are three RAS genes, which are the most commonly identified oncogenes, found in approximately 20-30% of all cancers.

Literature (4)
Pathways (2)
Gene Data

Ras GTPase Inhibitors

Cat. No. Product Name / Activity
7713 AMG 510
Potent and selective KRASG12C inhibitor
6857 BAY 293
Potent KRas/SOS1 interaction inhibitor
6791 BC-LI-0186
Leucyl-tRNA synthase (TRS)/Ras-related GTP-binding protein D (RagD) interaction inhibitor
6407 Fendiline Hydrochloride
Inhibits KRas localization to the plasma membrane; also L-type calcium channel blocker
5607 GNF 7
Ras signaling inhibitor; inhibits Ack1 and GCK
7928 KRpep-2d
Potent and selective KRASG12D inhibitor
6429 ML 210
Selectively kills mutant HRAS-expressing cells; glutathione peroxidase inhibitor; induces ferroptosis
7488 MRTX 849
Mutation-selective inhibitor of KRASG12C
5411 RBC8
RalA and RalB inhibitor
6111 Zoledronic Acid
Ras signaling inhibitor; also potent farnesyl diphosphate (FPP) synthase inhibitor


Cat. No. Product Name / Activity
7420 LC 2
Selective KRAS PROTAC®


Cat. No. Product Name / Activity
6906 BAY 293 Negative Control
Negative control for BAY 293 (Cat. No. 6857)
7421 LC 2 Epimer
Negative control for LC 2 (Cat. No. 7420)


Cat. No. Product Name / Activity
5424 Deltarasin
High affinity PDEδ-KRas interaction inhibitor; binds to PDEδ

RAS Structure and Function

There are three human RAS genes; HRAS, KRAS and NRAS, which encode four highly related 188-189 amino acid proteins, HRAS, KRAS4A, KRAS4B and NRAS. KRAS encodes two spice variants, with 4B being widely expressed and 4A more tissue restricted. The C-terminal 24/25 amino acid sequence exhibits the greatest divergence between the different isoforms and contain sequences that facilitate membrane interactions.

Ras proteins function as GDP-GTP regulated binary on-off switches that regulate a diverse network of cytoplasmic signaling networks. Wild-type Ras proteins exhibit low picomolar affinity for GDP and GTP function. Wild-type RAS proteins exist in an inactive GDP-bound state. Upon stimulation of cell surface receptors (e.g. EGFR) by extracellular stimuli, cytoplasmic signaling components are activated, which in turn activate RAS-selective guanine nucleotide exchange factors (RASGEFs; e.g., SOS1), stimulating rapid and transient GDP-GTP exchange and formation of the active GTP-bound protein. In the active GTP-bound state, Ras proteins have high affinity for Ras-binding domains on Ras effectors. Ras effectors include PI 3-K and RAF, which interact with multiple intracellular signaling pathway members, including MEK, ERK, and MYC as well as the PI3K/AKT/mTOR pathway.

The Ras active state is rapidly terminated by GTPase activating proteins (RASGAPs; e.g., neurofibromin) that stimulate the weak intrinsic GTPase activity of RAS, hydrolyzing the bound GTP to GDP, returning RAS to the inactive state.

Ras Effectors validated to drive RAS-dependent cancer growth

Figure 1: Ras Effectors. Schematic outlining the effectors validated to drive RAS-dependent cancer growth. Activated RAS-GTP recognizes RAS Binding (RBD) or RAS Association (RA) Domains. Image reproduced from: RAS Oncoproteins - Therapeutic Vulnerabilities. Bryant, KL et al. Tocris Scientific Review Series.

RAS and Cancer

RAS genes are the most frequently mutated oncogene family in cancer and are found in approximately 25% of all cancers. RAS proteins are therefore of interest as targets for the development of cancer treatments.

The three RAS genes are mutationally activated, however, the frequency of RAS missense mutations is not uniform among cancer types. For example, PDAC, the predominant form of pancreatic cancer, exhibits the highest frequency (95%) of RAS mutations, whereas in breast cancers mutant RAS genes are rare (<2%). In addition, the frequency of missense mutations is different for the three RAS genes: mutations in KRAS make up 85% of all RAS mutations in cancer, followed by NRAS (12%), while mutations in HRAS comprise only 3% of all cancer mutations. Whereas KRAS is the predominant RAS isoform mutated in PDAC (a form of pancreatic cancer), colorectal and lung adenocarcinoma, NRAS is the predominant isoform mutated in melanoma and acute myelogenous leukemia. Although rare overall, HRAS mutations are predominant in bladder and in head and neck squamous cell carcinomas.

RAS Inhibitors

RAS inhibitors have been developed that target RAS directly, modulate RAS subcellular localization and membrane association or that inhibit RAS effectors. Such compounds have enabled the exploration of RAS and its downstream signaling pathways. In addition, inhibitors of RAS function have been developed as cancer therapies.

Featured Product: LC 2

More recently Protein Degraders, such as LC 2 (Cat. No. 7420), have been developed which knockdown an entire protein, removing all possible functions - unlike an inhibitor which blocks or modifies a protein. LC 2 brings about the proteasomal degradation of mutant KRASG12C in cancer cells lines, resulting in suppression of MAPK signaling. This approach may help the further elucidation of the role of Ras, and has potential in treating cancers.

To learn more about LC 2, read our blog post: Development of a KRAS-targeting PROTAC®.

Resources for RAS GTPase Research

RAS Oncoproteins Webinar

RAS proteins function as binary on-off switches that regulate diverse cytoplasmic signaling networks. In cancer and developmental disorders (RASopathies), mutationally activated RAS proteins drive aberrant signal transduction. This webinar discusses the vulnerabilities of RAS that have been exploited for the development of pharmacologic inhibitors of RAS function.

Watch RAS Oncoproteins Webinar Now!
RAS Oncoproteins

External sources of pharmacological information for Ras GTPases :

    Literature for Ras GTPases

    Tocris offers the following scientific literature for Ras GTPases to showcase our products. We invite you to request* your copy today!

    *Please note that Tocris will only send literature to established scientific business / institute addresses.

    Cancer Metabolism Research Product Guide

    Cancer Metabolism Research Product Guide

    This product guide reviews some of the main areas in cancer metabolism research and lists around 150 products that can be used to investigate metabolic pathways in cancer including:

    RAS Oncoproteins Scientific Review

    RAS Oncoproteins Scientific Review

    Written by Kirsten L. Bryant, Adrienne D. Cox and Channing J. Der, this review provides a comprehensive overview of RAS protein function and RAS mutations in cancer. Key signaling pathways are highlighted and therapeutic vulnerabilities are explored. This review also includes a detailed section on RAS drug discovery and targeting synthetic lethal interactors of mutant RAS. Compounds available from Tocris are listed.

    Cell Cycle & DNA Damage Repair Poster

    Cell Cycle & DNA Damage Repair Poster

    In normal cells, each stage of the cell cycle is tightly regulated, however in cancer cells many genes and proteins that are involved in the regulation of the cell cycle are mutated or over expressed. This poster summarizes the stages of the cell cycle and DNA repair. It also highlights strategies for enhancing replicative stress in cancer cells to force mitotic catastrophe and cell death.

    Epigenetics in Cancer Poster

    Epigenetics in Cancer Poster

    This poster summarizes the main epigenetic targets in cancer. The dysregulation of epigenetic modifications has been shown to result in oncogenesis and cancer progression. Unlike genetic mutations, epigenetic alterations are considered to be reversible and thus make promising therapeutic targets.

    Pathways for Ras GTPases

    Akt Signaling Pathway

    Akt Signaling Pathway

    The Akt signaling pathway plays a key role in the mediation of protein synthesis, metabolism, proliferation and cell cycle progression. It may be referred to as a 'prosurvival' pathway.
    MAPK Signaling Pathway

    MAPK Signaling Pathway

    The mitogen-activated protein kinase pathway evokes an intracellular signaling cascade in response to extracellular stimuli such as heat and stress. It can influence cell division, metabolism and survival.

    Ras GTPases Gene Data

    Gene Species Gene Symbol Gene Accession No. Protein Accession No.
    HRas Human HRAS NM_176795 P01112
    Mouse Hras NM_008284 Q61411
    Rat Hras NM_001098241 NP_001091711
    KRas Human KRAS NM_033360 P01116
    Mouse Kras NM_021284 P32883
    Rat Kras NM_031515 NP_113703
    NRas Human NRAS NM_002524 P01111
    Mouse Nras NM_010937 P08556
    Rat Nras NM_080766 NP_542944
    RalA Human RALA NM_005402 P11233
    Mouse Rala NM_019491 P63321
    Rat Rala NM_031093 NP_112355
    RalB Human RALB NM_002881 P11234
    Mouse Ralb NM_022327 Q9JIW9
    Rat Ralb NM_053821 NP_446273