Related Experiment Video

Updated: Mar 7, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

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

Published on: July 17, 2019

6.6K

Divergent effects of intrinsically active MEK variants on developmental Ras signaling

Yogesh Goyal1,2,3, Granton A Jindal1,2,3, José L Pelliccia3

  • 1Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey, USA.

Nature Genetics
|February 7, 2017
PubMed

Insights

RASopathies, developmental disorders, can result from Ras pathway mutations. Surprisingly, MEK variants can either increase or decrease pathway activation, depending on cellular context, impacting disease phenotypes.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Genetics

Background:

  • RASopathies are human developmental disorders linked to germline mutations in Ras pathway components.
  • These conditions present diverse phenotypes, including cardiac defects and neurocognitive delays.
  • The precise signaling alterations in developing tissues during RASopathies are not fully understood.

Purpose of the Study:

  • To investigate the in vivo signaling changes in the Ras pathway caused by mutations in MAP2K1 (MEK).
  • To quantify Ras pathway activation levels in developing tissues using spatiotemporal assays.
  • To elucidate the relationship between MEK variants and RASopathy phenotypes.

Main Methods:

  • Utilized Drosophila melanogaster (fruit fly) and Danio rerio (zebrafish) models.
  • Employed assays with spatiotemporal resolution to measure Ras pathway signaling.
  • Analyzed signaling changes resulting from specific MAP2K1 mutations.

Main Results:

  • Discovered that intrinsically active MEK variants can paradoxically increase or decrease Ras pathway activation in vivo.
  • Demonstrated that the effect of MEK variants on pathway activation is context-dependent.
  • Identified a novel mechanism influencing Ras signaling levels in developmental disorders.

Conclusions:

  • Some RASopathy phenotypes may arise from both elevated and reduced Ras signaling levels.
  • Cellular context plays a crucial role in determining the impact of MEK variants on Ras pathway activity.
  • Findings challenge the assumption of uniformly increased Ras pathway activation in all RASopathies.

More Related Videos

Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development09:32

Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development

Published on: June 15, 2017

9.3K
Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans08:12

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

Published on: October 5, 2020

3.4K

Related Concept Videos

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...
8.9K
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...
7.4K
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...
7.6K
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:
5.6K
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...
5.0K
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...
6.0K