Mutant ras-induced proliferation of human thyroid epithelial cells requires three effector pathways

Related Experiment Video

Updated: Aug 22, 2026

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

Ali Bounacer1, Alex McGregor, Julia Skinner

  • 1Cancer Research UK Laboratories, Department of Pathology, University of Wales College of Medicine, Cardiff CF14 4XN, UK.

Oncogene
|September 14, 2004
PubMed

Insights

Ras mutations drive tumor initiation. In thyroid cells, Ras needs three pathways—MAPK, PI3K, and RalGEF—to activate proliferation, highlighting cellular context importance.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Ras mutations are early events in epithelial tumors, including thyroid cancer.
  • Ras-induced proliferation in human thyroid cells requires MAP kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways, but these are insufficient alone.

Purpose of the Study:

  • To investigate the role of additional Ras effector pathways in Ras-induced proliferation in primary human thyroid epithelial cells.
  • To determine if RalGEF activation by Ras is necessary for proliferation and if it cooperates with MAPK and PI3K pathways.

Main Methods:

  • Utilized primary human thyroid epithelial cells to model Ras-driven tumor initiation.
  • Analyzed the activation status of MAPK, PI3K, and RalGEF effector pathways in response to Ras.
  • Assessed the necessity and sufficiency of these pathways for Ras-induced cell proliferation.

Main Results:

  • Ras activates the RalGEF effector pathway in human thyroid cells.
  • RalGEF activation is essential for Ras-induced proliferation.
  • The combined activation of MAPK, PI3K, and RalGEF pathways fully reproduces Ras-induced proliferation.

Conclusions:

  • Ras-induced proliferation in normal human thyroid epithelial cells requires the coordinated activation of three distinct effector pathways: MAPK, PI3K, and RalGEF.
  • This finding indicates a more stringent control of cell proliferation in this specific cellular context compared to cell lines.
  • The cellular context is crucial for accurately modeling Ras-induced tumor development.

More Related Videos

Spontaneous Murine Model of Anaplastic Thyroid Cancer05:39

Spontaneous Murine Model of Anaplastic Thyroid Cancer

Published on: February 3, 2023

Induction and Analysis of Epithelial to Mesenchymal Transition10:37

Induction and Analysis of Epithelial to Mesenchymal Transition

Published on: August 27, 2013

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...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
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:
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...