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MEK/ERK regulates adherens junctions and migration through Rac1
Ramesh M Ray1, Rajiv J Vaidya, Leonard R Johnson
1Department of Physiology, The University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. rray@physiol.utmem.edu
Cell Motility and the Cytoskeleton
|December 22, 2006
Summary
Polyamine depletion inhibits intestinal cell migration by preventing Rac1 activation, disrupting cell-cell contacts and E-cadherin expression. This pathway involves MEK1/ERK signaling and Tiam1 activation of Rac1.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Polyamine depletion using alpha-difluoromethyl ornithine (DFMO) inhibits intestinal epithelial cell migration by preventing Rac1 activation and actin cortex formation.
- Epidermal Growth Factor (EGF) signaling is crucial for cell migration and junction dynamics.
Purpose of the Study:
- To investigate the role of MEK1/ERK and Rac1 in regulating cell-cell contacts and migration during polyamine depletion.
- To elucidate the upstream regulators of Rac1 activation in intestinal epithelial cells.
Main Methods:
- Utilized DFMO for polyamine depletion.
- Employed MEK inhibitors (U0126) and constitutively active MEK1 (CA-MEK) and Rac1 (CA-Rac1) expression.
- Assessed cell-cell contacts, actin cytoskeleton organization, and protein expression (E-cadherin, beta-catenin) via immunolocalization, western blotting, and subcellular fractionation.
- Investigated the role of Tiam1 using a specific inhibitor (NSC23766).
Main Results:
- EGF-induced Rac1 activation, cell dissociation, and migration were observed in both control and polyamine-depleted cells.
- MEK inhibition prevented EGF-induced Rac1 activation and junction disruption.
- CA-MEK expression altered cell-cell contacts in both conditions.
- CA-Rac1 expression restored beta-catenin localization, prevented actin cortex formation, and induced stress fibers in polyamine-depleted cells.
- Tiam1 inhibition mimicked the effects of polyamine depletion on beta-catenin and actin.
- Polyamine depletion reduced E-cadherin and beta-catenin expression.
Conclusions:
- EGF signaling through MEK1/ERK activates Rac1, regulating cell-cell contacts.
- Polyamine depletion decreases intestinal cell migration by inhibiting Tiam1-mediated Rac1 activation, leading to reduced beta-catenin and E-cadherin expression and impaired cell-cell contacts.
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