MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42

Related Experiment Video

Updated: Aug 13, 2026

Assaying Protein Kinase Activity with Radiolabeled ATP
08:05

Assaying Protein Kinase Activity with Radiolabeled ATP

Published on: May 26, 2017

G R Fanger1, N L Johnson, G L Johnson

  • 1Division of Basic Sciences, National Jewish Medical and Research Center, Denver, CO 80206, USA.

The EMBO Journal
|August 15, 1997
PubMed

Insights

MEK kinases (MEKKs) regulate MAP kinases like JNKs and ERKs. Specific MEKKs, localized to different cellular compartments, control distinct MAPK pathways and are involved in Rac/Cdc42 signaling to JNK.

Area of Science:

  • Cellular signaling pathways
  • Molecular and cell biology
  • Signal transduction

Background:

  • Mitogen-activated protein kinase (MAPK) pathways are crucial for cellular responses.
  • MEK kinases (MEKKs) are key regulators upstream of JNK and ERK pathways.
  • Understanding MEKK function and localization is vital for deciphering MAPK signaling.

Purpose of the Study:

  • To investigate the differential subcellular localization of MEKK1-4.
  • To determine the specific roles of MEKKs in regulating JNK and ERK activation.
  • To elucidate the involvement of MEKKs in small GTPase signaling.

Main Methods:

  • Confocal immunofluorescence microscopy to visualize MEKK localization in COS cells.
  • Activation studies using epidermal growth factor (EGF).
  • Use of kinase-inactive MEKK mutants to assess pathway inhibition.
  • Co-immunoprecipitation to study interactions with small GTP-binding proteins (Rac and Cdc42).

Main Results:

  • MEKK1 localized to the nucleus and post-Golgi structures; MEKK2 and 4 localized to Golgi-associated vesicles.
  • MEKK1 and 2 were activated by EGF, influencing JNK activity.
  • MEKK1, but not others, inhibited EGF-stimulated ERK activity.
  • MEKK1 and 4, but not MEKK2 and 3, associated with Rac/Cdc42 and regulated their JNK activation.
  • MEKKs are independent of the PAK-regulated JNK pathway.

Conclusions:

  • Specific MEKKs regulate distinct MAPK pathways (JNK, ERK) in different cellular compartments.
  • MEKK1 and 4 are involved in Rac/Cdc42-mediated JNK activation, independent of PAK.
  • Differential MEKK localization and small GTP-binding protein interactions enable localized MAPK regulation.

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

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans08:12

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

Published on: October 5, 2020

Related Concept Videos

M-Cdk Drives Transition Into Mitosis02:15

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
Cell Polarization by Rho Proteins01:21

Cell Polarization by Rho Proteins

Cell polarity is the asymmetric distribution of cellular and membrane components, making one side of the cell different from the other. This polarity is essential to many processes such as embryogenesis, axon migration, glucose transport across epithelial cells, and directional cell migration. A migrating cell responds to intracellular or extracellular signals via molecular cascades that reorganize the actin cytoskeleton to establish this polarity. In these cells, the Rho family proteins Cdc42,...
Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
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:
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...