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The Ras Gene

The Ras Gene

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.
Ras is a...

Small GTPases - Ras and Rho

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MAPK Signaling Cascades

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...

Rab Proteins

Rab Proteins

Rab proteins constitute the largest family of monomeric GTPases, of which 70 members are present in humans. Rab proteins and their effectors regulate consecutive stages of vesicle transport such as vesicle transport, docking, and fusion to the correct recipient membrane.
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...

Rous Sarcoma Virus (RSV) and Cancer

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Rous Sarcoma virus or RSV was discovered by F. Peyton Rous in the year 1911 as a filterable transmissible agent that could cause tumors in chickens. He won a Nobel Prize for this discovery in 1966. His experiments clearly demonstrated that some cancers could be caused by infectious agents and led to the discovery of many more cancer-causing viruses in animals as well as humans.
RSV is a retrovirus that contains two copies of a plus-strand RNA genome. Its genome consists of four main open...

Rab Cascades

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Rab GTPases act in a regulated cascade during membrane fusion, helping the lipid bilayers mix. The Rab family of proteins are active when bound to GTP, and inactive when bound to GDP. Hence, they act as guanine nucleotide-dependent molecular switches. Rab-GTP recognizes and binds to long or short-range tethering proteins to capture the target vesicle. These tethers coordinate with SNAREs on the vesicle and the target membrane to assemble the trans SNARE complex that locks the mixing bilayers.

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Related Experiment Video

Updated: Aug 12, 2025

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

Published on: October 5, 2020

Origin and evolution of RAS oncoprotein membrane targeting.

Antonio García-España¹, Mark R Philips²

¹Bionos Biotech SL; Biopolo Hospital La Fe, Valencia, Spain.

Research Square

|January 30, 2023

Summary

The evolution of RAS oncogenes reveals KRAS as the ancestral gene, with duplications generating HRAS, NRAS, and KRASBL. These evolutionary events shaped RAS isoforms, suggesting distinct functions critical for oncoprotein activity.

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Area of Science:

Evolutionary biology
Molecular genetics
Cancer research

Background:

The RAS oncogene family, including KRAS, HRAS, and NRAS, comprises homologous genes encoding small GTPases.
RAS oncoproteins feature a G-domain and a hypervariable region (HVR) for membrane targeting.
The evolutionary origins and diversification of RAS isoforms remain underexplored.

Approach:

Phylogenetic analysis to trace the evolutionary history of RAS genes.
Identification and characterization of gene duplication events and alternative splicing.
Comparative genomics to study conserved and divergent features across species.

Key Points:

KRAS is the basal oncogene; its duplication yielded HRAS in early vertebrates.
Further duplications generated NRAS and KRASBL, with KRAS4A arising from NRAS exon insertion into KRAS.
Conserved motifs like polybasic regions (PBR1, PBR2) and modified CaaX motifs suggest functional adaptations in RAS isoforms.

Conclusions:

The persistence of four RAS isoforms over 400 million years strongly indicates specialized, differential functions.
Evolutionary modifications, including lipid anchor alterations, are critical for RAS oncoprotein activity.
Understanding RAS evolution provides insights into oncogenesis and potential therapeutic targets.