MEK1 restores migration of polyamine-depleted cells by retention and activation of Rac1 in the cytoplasm

Vaidya, R. J.; Ray, Ramesh M.; Johnson, Leonard R.

doi:10.1152/ajpcell.00290.2004

Cited by 35 publications

(29 citation statements)

References 57 publications

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“…Injury-induced increases in the production of EGF and over-expression of the EGFR have been observed during mucosal repair [Tarnawski et al, 1992]. EGF activates MEK1, and we have shown that expression of CA-MEK1 restores migration in polyamine-depleted cells [Vaidya et al, 2005]. We have previously reported that maximal polyamine depletion occurs after 4 days of treatment with 5 mM DFMO [Ray et al, 2000].…”

Section: Discussionmentioning

confidence: 61%

“…Previous reports from our laboratory have shown that polyamine-depletion inhibited migration by preventing the activation of Rho family GTPases and subsequent cytoskeletal remodeling [McCormack et al, 1993;Ray et al, 2002]. We have also shown that sustained activation of MEK1 restored migration of polyamine-depleted cells by activating Rac1 to cause the reorganization of cortical actin into stress fibers [Vaidya et al, 2005]. Constitutively active (CA) MEK expressing cells migrated as solitary cells rather than as a monolayer sheet suggesting that MEK regulates the assembly and disassembly of adherens junctions.…”

Section: Introductionmentioning

confidence: 54%

“…We have shown earlier that EGF increased migration in both control and polyamine depleted cells, however, it did not restore the migration rate of polyamine-depleted cells to that of control cells. In addition, CA-MEK significantly increased migration in both normal and polyamine-depleted cells [Vaidya et al, 2005]. CA-MEK expression decreased cell-cell contact (Fig.…”

Section: Discussionmentioning

confidence: 79%

“…The expression of a DN-Rac mutant decreased cadherin-mediated cell-cell contacts in both primary keratinocytes and MDCKII cells [Hirano et al, 1992;Jou and Nelson, 1998]. We previously found that polyamine depletion decreased Rac1 activity [Ray et al, 2003], and the expression of CA-MEK1 restored Rac1 activity, migration and the ACS in these cells [Vaidya et al, 2005]. EGF also increased the activities of MEK1 and Rac1 and migration (Figs.…”

Section: Discussionmentioning

confidence: 86%

“…We have shown that CA-MEK1 expression increased migration via Rac1 in control and polyamine depleted cells [Vaidya et al, 2005]. We examined the cell-cell contacts in control cells and DFMO, and DFMO plus putrescine groups (Fig.…”

Section: Ca-mek1 Alters the Organization Of Cell-cell Adhesionsmentioning

confidence: 99%

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MEK/ERK regulates adherens junctions and migration through Rac1

Ray

Vaidya

Johnson

2006

Cell Motil. Cytoskeleton

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Polyamine depletion with the ornithine decarboxylase inhibitor a-difluoromethyl ornithine (DFMO), prevents Rac1 activation causing the formation of a thick actin cortex at the cell periphery and inhibits migration of intestinal epithelial cells. In the present study, we demonstrate that MEK activation by EGF increased Rac1 activation, dissociation of intercellular contacts, and migration in both control and polyamine-depleted cells, while U0126, a specific inhibitor of MEK1, prevented disruption of junctions as well as EGF-induced Rac1 activation. Constitutively active MEK1 (CA-MEK) expression altered cell-cell contacts in control and polyamine depleted cells. The expression of constitutively active Rac1 (CA-Rac1) restored b-catenin to the cell periphery and prevented the formation of actin cortex and caused the appearance of F-actin stress fibers in polyamine-depleted cells. Inhibition of Rac activation by NSC23766, a specific inhibitor of Tiam1, an upstream guanidine nucleotide exchange factor for Rac1, reproduced the b-catenin localization and actin structure of polyamine-depleted cells. Tiam1 localized more extensively with b-catenin at the cell periphery in CA-Rac1 cells compared to vector cells. Polyamine depletion decreased the expression of E-cadherin to a greater extent compared to b-catenin. Subcellular fractionation further confirmed our immuno-localization and western blotting observations. These data suggest that EGF acting through MEK1/ERK to activate Rac1 regulates cell-cell contacts. Thus, decreased migration in polyamine depleted cells may be due to the inhibition of Tiam1 activation of Rac1 and the subsequent decreased expression of b-catenin and E-cadherin leading to reduced cell-cell contacts. Cell Motil.

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Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 86%

Section: Ca-mek1 Alters the Organization Of Cell-cell Adhesionsmentioning

confidence: 99%

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MEK/ERK regulates adherens junctions and migration through Rac1

Ray

Vaidya

Johnson

2006

Cell Motil. Cytoskeleton

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Mammalian polyamine metabolism and function

2009

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SummaryPolyamines are ubiquitous small basic molecules that play multiple essential roles in mammalian physiology. Their cellular content is highly regulated and there is convincing evidence that altered metabolism is involvement in many disease states. Drugs altering polyamine levels may therefore have a variety of important targets. This review will summarize the current state of understanding of polyamine metabolism and function, the regulation of polyamine content, and heritable pathological conditions that may be derived from altered polyamine metabolism.

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Gab2 requires membrane targeting and the met binding motif to promote lamellipodia, cell scatter, and epithelial morphogenesis downstream from the met receptor

Frigault

Naujokas

Park

2007

Journal Cellular Physiology

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Gab1 and Gab2 are conserved scaffolding proteins that amplify and integrate signals stimulated by many growth factor receptors including the Met receptor. Gab1 acts to diversify the signal downstream from Met through the recruitment of multiple signaling proteins, and is essential for epithelial morphogenesis. However, whereas Gab1 and Gab2 are both expressed in epithelial cells, Gab2 fails to support a morphogenic response. We demonstrate that Gab1 and Gab2 are divergent in their function whereby Gab1, but not Gab2, promotes lamellipodia formation, and is localized to the membrane of lamellipodia upon Met activation. We have identified activation of ERK1/2 as a requirement for lamellipodia formation. Moreover, activated ERK1/2 are localized to lamellipodia in Gab1 expressing cells but not in cells that overexpress Gab2. By structure-function studies, we identify that enhanced membrane localization conferred through the addition of a myristoylation signal, together with the addition of the direct Met binding motif (MBM) from Gab1, are required to promote lamellipodia and confer a morphogenic signaling response to Gab2. Moreover, the morphogenesis competent myristoylated Gab2MBM promotes localization of activated ERK1/2 to the leading edge of lamellipodia in a similar manner to Gab1. Hence, subcellular localization of the Gab scaffold, as well as the ability of Gab to interact directly with the Met receptor, are both essential components of the morphogenic signaling response which involves lamellipodia formation and the localization of ERK1/2 activation in membrane ruffles.

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MEK1 restores migration of polyamine-depleted cells by retention and activation of Rac1 in the cytoplasm

Abstract: Vaidya, Rajiv J., Ramesh M. Ray, and Leonard R. Johnson. MEK1 restores migration of polyamine-depleted cells by retention and activation of Rac1 in the cytoplasm.

Cited by 35 publications

References 57 publications

MEK/ERK regulates adherens junctions and migration through Rac1

MEK/ERK regulates adherens junctions and migration through Rac1

Mammalian polyamine metabolism and function

Gab2 requires membrane targeting and the met binding motif to promote lamellipodia, cell scatter, and epithelial morphogenesis downstream from the met receptor

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