Related Experiment Video

Updated: Aug 16, 2026

Bioluminescence Resonance Energy Transfer (BRET)-Based Assay for Measuring Interactions of CRAF with 14-3-3 Proteins in Live Cells
06:44

Bioluminescence Resonance Energy Transfer (BRET)-Based Assay for Measuring Interactions of CRAF with 14-3-3 Proteins in Live Cells

Published on: March 1, 2024

A conditional feedback loop regulates Ras activity through EphA2

Madhu Macrae1, Richard M Neve, Pablo Rodriguez-Viciana

  • 1Cancer Research Institute and Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143, USA.

Cancer Cell
|August 16, 2005
PubMed

Insights

The EphA2 receptor tyrosine kinase, often overexpressed in cancers like breast cancer, forms a negative feedback loop with the Ras-Raf-MAPK pathway to regulate cell growth. This interaction

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • EphA2 receptor tyrosine kinase is overexpressed in numerous cancers, notably 40% of breast cancers.
  • The Ras-Raf-MAPK pathway is a critical signaling cascade involved in cell proliferation and survival.

Purpose of the Study:

  • To investigate the regulatory relationship between EphA2 and the Ras-Raf-MAPK pathway.
  • To elucidate the role of EphA2 and its ligand ephrin-A1 in breast cancer cell lines.

Main Methods:

  • Analysis of EphA2 as a direct transcriptional target of the Ras-Raf-MAPK pathway.
  • Assessment of ligand-stimulated EphA2's effect on Ras activation.
  • Examination of EphA2 and ephrin-A1 expression patterns in breast cancer cell lines.

Main Results:

  • EphA2 is a direct transcriptional target of the Ras-Raf-MAPK pathway, forming a negative feedback loop that attenuates Ras activity.
  • Expression of EphA2 and its ligand ephrin-A1 is mutually exclusive in breast cancer cell lines.
  • The MAPK pathway inhibits ephrin-A1 expression, while ephrin-A1 expression inhibits EphA2 levels, creating a reciprocal expression pattern.

Conclusions:

  • The EphA2-Ras-Raf-MAPK signaling axis and its reciprocal receptor-ligand expression pattern play a significant role in cancer development.
  • Disruption of this negative feedback loop may contribute to oncogenesis.

More Related Videos

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

Development and Application of Rapamycin-regulated Tyrosine Phosphatases06:56

Development and Application of Rapamycin-regulated Tyrosine Phosphatases

Published on: September 6, 2024

Related Concept Videos

The Ras Gene02:38

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 superfamily...
MAPK Signaling Cascades01:07

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...
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

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:
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

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 the...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

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...