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Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

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Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
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The Ras Gene02:38

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The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
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GTPases and their Regulation02:14

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Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒  small G-proteins consisting of a single domain and large multi-domain G-proteins.
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Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
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Amplifying Signals via Enzymatic Cascade01:22

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When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
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Related Experiment Video

Updated: Apr 23, 2026

Comparing the Affinity of GTPase-binding Proteins using Competition Assays
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Comparing the Affinity of GTPase-binding Proteins using Competition Assays

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Revisiting RAS family GTPase signaling: effector selectivity and oncogenic bypass.

Dhirendra K Simanshu1, Frank McCormick1,2

  • 1NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, U.S.A.

The Biochemical Journal
|April 22, 2026
PubMed
Summary
This summary is machine-generated.

RAS GTPases exhibit distinct effector preferences, with canonical RAS binding RAF, RRAS engaging PI3Kα, and RAP activating RalGDS. Oncogenic mutations override these preferences, broadening downstream signaling in cancers.

Keywords:
KRASRAF1RASRRAS2Rap1phosphoinositide 3-kinase

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Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Biology

Background:

  • Canonical RAS proteins were thought to uniformly bind effectors like RAF, PI3Kα, and RalGDS.
  • Recent findings suggest distinct effector-binding preferences among RAS subfamilies.

Purpose of the Study:

  • To elucidate the specific effector-binding preferences of different RAS GTPase subfamilies.
  • To understand how oncogenic mutations disrupt these preferences and alter downstream signaling.

Main Methods:

  • Quantitative binding assays to measure affinity between RAS proteins and effectors.
  • Structural analysis of effector recognition by RAS GTPases.
  • Analysis of oncogenic RAS mutations and their impact on effector engagement.

Main Results:

  • Canonical RAS (KRAS, HRAS, NRAS) preferentially binds RAF kinases.
  • RRAS subfamily (RRAS2, MRAS) shows high affinity for PI3Kα.
  • RAP subfamily (RAP1A, RAP1B) primarily engages RalGDS.
  • Oncogenic mutations (G12, G13, Q61) disrupt normal hierarchy, enabling canonical RAS to bind PI3Kα and RalGDS.
  • Certain mutations (e.g., KRAS-G12D/V) confer neomorphic PI3Kα binding.

Conclusions:

  • RAS GTPase effector binding is selective, establishing a signaling hierarchy in normal cells.
  • Oncogenic mutations override selectivity, leading to aberrant effector engagement and broadened signaling in cancer.
  • This framework explains RAS-driven cancer signaling by understanding both normal preferences and oncogenic disruptions.