Related Experiment Video
Updated: Jul 4, 2026
09:58
RhoC GTPase Activation Assay
Published on: August 22, 2010
ERK5 promotes Src-induced podosome formation by limiting Rho activation
Mark Schramp1, Olivia Ying, Tai Young Kim
1Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.
The Journal of Cell Biology
|June 25, 2008
Summary
Extracellular signal-regulated kinase 5 (ERK5) promotes Src-induced podosome formation by regulating Rho GTPase signaling. ERK5 limits Rho activation by inducing RhoGAP7, which is crucial for cell invasion.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Src activity is linked to tumorigenesis and the formation of invasive podosomes.
- Podosome formation involves Rho GTPases and actin cytoskeleton reorganization.
- Src signaling influences gene expression via mitogen-activated protein kinase (MAPK) pathways.
Purpose of the Study:
- To investigate the role of MAPK signaling, specifically ERK5, in regulating podosome formation.
- To understand the mechanism by which ERK5 influences Src-induced cell invasion.
Main Methods:
- Utilized Src-transformed fibroblasts and ERK5-deficient cells.
- Assessed RhoA activation, Rho-kinase inhibition (Y27632), and podosome formation.
- Investigated the role of transcription factor myocyte enhancing factor 2C and RhoGAP7/DLC-1 expression.
Main Results:
- ERK5 is constitutively activated in Src-transformed cells.
- ERK5 deficiency in v-Src expressing cells resulted in increased RhoA activation, cellular retraction, and impaired podosome formation.
- Rho-kinase inhibition restored cellular extension and podosome formation in ERK5-deficient cells.
- ERK5 induced RhoGAP7 expression via myocyte enhancing factor 2C, and RhoGAP7 restored podosome formation in ERK5-deficient cells.
Conclusions:
- ERK5 is essential for Src-induced podosome formation and cell invasion.
- ERK5 promotes podosome formation by upregulating RhoGAP7, which suppresses RhoA activation.
- This pathway highlights a novel mechanism linking MAPK signaling to cytoskeletal dynamics and cancer progression.
Related Concept Videos
01:24Small 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:
Three regulatory proteins control their activity:
01:21Cell 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,...
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...
02:38The 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...
Ras is a superfamily...
01:14Rab Proteins
Rab proteins constitute the largest family of monomeric GTPases, of which 70 members are present in humans. Rab proteins and their effectors regulate consecutive stages of vesicle transport such as vesicle transport, docking, and fusion to the correct recipient membrane.
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...
01:26Receptor 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...