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Updated: Jul 29, 2025

Using the E1A Minigene Tool to Study mRNA Splicing Changes
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Differential functions of the KRAS splice variants

Juan Kochen Rossi1, Cristina Nuevo-Tapioles1, Mark R Philips1

  • 1Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, U.S.A.

Biochemical Society Transactions
|May 24, 2023
PubMed

Insights

KRAS proteins are key in cell signaling and cancer. This review explores the distinct roles of KRAS4A and KRAS4B splice variants, highlighting KRAS4A

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Cancer Genetics

Background:

  • RAS proteins are crucial GTPases regulating cell growth and differentiation.
  • KRAS is frequently mutated in human cancers, making it a significant oncogene.
  • Alternative splicing of KRAS pre-mRNA yields KRAS4A and KRAS4B isoforms with distinct C-terminal hypervariable regions.

Approach:

  • This mini-review synthesizes current research on KRAS splice variants.
  • It examines the evolutionary origin and differential functions of KRAS4A and KRAS4B.
  • The review highlights splice variant-specific interactions and cellular roles, such as KRAS4A's regulation of hexokinase I.

Key Points:

  • KRAS4A and KRAS4B isoforms differ in their C-terminal hypervariable regions, affecting subcellular localization and membrane association.
  • KRAS4A, though less abundant, exhibits unique functions and expression in tumors.
  • Emerging evidence suggests non-overlapping roles for these splice variants, challenging the notion of KRAS4B as the sole principal isoform.

Conclusions:

  • Understanding the differential functions of KRAS4A and KRAS4B is critical for cancer research.
  • KRAS4A's specific roles, including its regulation of hexokinase I, warrant further investigation.
  • This review provides an overview of the evolutionary and functional divergence of KRAS splice variants.
Keywords:
KRASKRAS4AKRAS4Balternative splicingevolutiononcogene

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