Related Experiment Video
Updated: Jul 11, 2026
07:55
Subcellular Fractionation for ERK Activation Upon Mitochondrial-derived Peptide Treatment
Published on: September 25, 2017
MEK1 and MEK2 regulate distinct functions by sorting ERK2 to different intracellular compartments
Ellen Skarpen1, Liv Ingrid Flinder, Carola Maria Rosseland
1Laboratory for Toxicopathology, Institute of Pathology, Rikshospitalet-Radiumhospitalet Medical Centre, University Hospital, N-0027 Oslo, Norway. ellen.skarpen@medisin.uio.no
Summary
The study reveals how ERK2
Area of Science:
- Cellular signaling pathways
- Molecular mechanisms of cell response
- Signal transduction in cell growth and survival
Background:
- ERK2 (extracellular signal-regulated kinase 2) is a key kinase in cell signaling.
- The intracellular localization of ERK2 influences its biological functions.
- MEK1 and MEK2 are upstream activators of ERK2, but their roles in ERK2 localization and function are not fully understood.
Purpose of the Study:
- To elucidate the mechanism by which ERK2 is sorted to different intracellular compartments.
- To determine how ERK2 localization dictates cellular responses, specifically proliferation versus survival.
- To investigate the role of MEK1 and MEK2 in controlling ERK2 localization and function.
Main Methods:
- Investigated ERK2 localization upon activation by MEK1 versus MEK2.
- Utilized a nuclear export site to alter ERK2 localization and assess functional changes.
- Examined the role of specific phosphorylation sites (S298, T292) in MEK1 and their impact on MEK1-ERK2 interaction and ERK2 translocation.
Main Results:
- MEK1-activated ERK2 localized to the nucleus, promoting proliferation.
- MEK2-activated ERK2 remained in the cytoplasm, promoting survival.
- Altering ERK2's localization to the cytoplasm using a nuclear export site switched MEK1's function from proliferation to survival.
- MEK1-mediated ERK2 nuclear translocation and proliferation depend on phosphorylation of S298 and T292 sites.
- p21-activated kinase phosphorylates S298, enhancing MEK1-ERK2 association, while ERK2 phosphorylates T292, releasing active ERK2 from MEK1.
- These phosphorylation events are adhesion-dependent in MEK1 but not MEK2.
Conclusions:
- ERK2 intracellular localization is a critical determinant of whether cells undergo proliferation or survival in response to growth factors.
- MEK1 and MEK2 differentially regulate ERK2 localization, leading to distinct cellular outcomes.
- Adhesion-dependent phosphorylation of MEK1 at S298 and T292 sites controls ERK2 nuclear translocation, partially explaining the requirement for adhesion in growth factor-induced proliferation.
Related Concept Videos
01:07MAPK 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...
01:15Receptor Downregulation in MVBs
Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
02:15M-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...
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...
02:23Master Transcription Regulators
Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
01:45ER Retrieval Pathway
In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
02:38Mitogens 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...