Related Experiment Video
Updated: Jun 8, 2025
15:05
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
8.5K
Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS
Jason J Kwon1,2,3, Julien Dilly1,2,3, Shengwu Liu1,2
1Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA.
Biorxiv : the Preprint Server for Biology
|November 1, 2024
Summary
Deep mutational scanning comprehensively mapped KRAS variants, revealing novel oncogenic alleles and mechanisms of inactivation. This work provides a resource for interpreting KRAS mutations and developing targeted cancer therapies.
Area of Science:
- Oncogenic signaling pathways
- Molecular mechanisms of cancer
Background:
- KRAS is a key oncoprotein frequently mutated in human cancers.
- Understanding KRAS variant function is critical for cancer therapy.
Purpose of the Study:
- To comprehensively map the functional landscape of KRAS variants.
- To identify novel oncogenic KRAS alleles and understand their transforming potential.
- To elucidate mechanisms of KRAS inactivation for therapeutic targeting.
Main Methods:
- Deep mutational scanning (DMS) of wild-type and KRASG12D alleles.
- Biochemical and structural analyses of identified KRAS variants.
- Development of a model for KRAS mutation frequency in cancer.
Main Results:
- Defined the oncogenic potential of nearly all KRAS variants, identifying novel transforming alleles.
- Established a model linking mutation frequency to transforming potential, mutational probability, and tissue-specific signatures.
- Identified protein instability and conformational rigidity as mechanisms for KRAS inactivation.
Conclusions:
- KRAS variant landscape characterized, aiding clinical interpretation.
- Mechanisms of oncogenic KRAS inactivation elucidated for therapeutic exploitation.
- Provides a foundational resource for KRAS-driven cancer research.
Related Concept Videos
02:38The Ras Gene
6.2K
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...
Ras is a...
6.2K
01:33Cancer-Critical Genes I: Proto-oncogenes
8.7K
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
8.7K
01:24Small GTPases - Ras and Rho
3.9K
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:
Three regulatory proteins control their activity:
3.9K
03:03mTOR Signaling and Cancer Progression
3.7K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.7K
01:12Loss of Tumor Suppressor Gene Functions
4.7K
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
4.7K
01:22Amplifying Signals via Enzymatic Cascade
8.3K
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...
8.3K