ERK-MAPK Drives Lamellipodia Protrusion by Activating the WAVE2 Regulatory Complex

Mendoza, Michelle C.; Er, Ekrem Emrah; Zhang, Wenjuan; Ballif, Bryan A.; Elliott, Hunter; Danuser, Gaudenz; Blenis, John

doi:10.1016/j.molcel.2011.02.031

Cited by 153 publications

(215 citation statements)

References 51 publications

(86 reference statements)

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“…Indeed, the recruitment of Shp2 to the plasma membrane was found to promote the dephosphorylation of Rho kinase II (ROCKII), resulting in modulation of RhoAinduced cell rounding (41). Based on the known roles of the Ras/ MAPK pathway in cell motility in diverse systems (42), these findings indicate that RSK likely regulates the involvement of Shp2 in both of these pathways to promote a change in cell shape and cell motility.…”

Section: Discussionmentioning

confidence: 95%

Gab2 Phosphorylation by RSK Inhibits Shp2 Recruitment and Cell Motility

Zhang

Lavoie

Fort

et al. 2013

Molecular and Cellular Biology

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The scaffolding adapter protein Gab2 (Grb2-associated binder) participates in the signaling response evoked by various growth factors and cytokines. Gab2 is overexpressed in several human malignancies, including breast cancer, and was shown to promote mammary epithelial cell migration. The role of Gab2 in the activation of different signaling pathways is well documented, but less is known regarding the feedback mechanisms responsible for its inactivation. We now demonstrate that activation of the Ras/mitogen-activated protein kinase (MAPK) pathway promotes Gab2 phosphorylation on basic consensus motifs. More specifically, we show that RSK (p90 ribosomal S6 kinase) phosphorylates Gab2 on three conserved residues, both in vivo and in vitro. Mutation of these phosphorylation sites does not alter Gab2 binding to Grb2, but instead, we show that Gab2 phosphorylation inhibits the recruitment of the tyrosine phosphatase Shp2 in response to growth factors. Expression of an unphosphorylatable Gab2 mutant in mammary epithelial cells promotes an invasion-like phenotype and increases cell motility. Taken together, these results suggest that RSK is part of a negative-feedback loop that restricts Gab2-dependent epithelial cell motility. On the basis of the widespread role of Gab2 in receptor signaling, these findings also suggest that RSK plays a regulatory function in diverse receptor systems.

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Section: Discussionmentioning

confidence: 95%

Gab2 Phosphorylation by RSK Inhibits Shp2 Recruitment and Cell Motility

Zhang

Lavoie

Fort

et al. 2013

Molecular and Cellular Biology

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“…These localization determinants may include RhoA and Cdc42; it is suggested that during PBE, Cdc42 drives dynamic F-actin through the Arp2/3 complex, which causes membrane protrusion, and RhoA drives stable F-actin, which restricts this protrusion and exerts constriction at cleavage furrow (Zhang et al, 2008;Maddox et al, 2012). Activation of Arp2/3 during lamellipodial protrusion involves ERK-MAPK activity (Mendoza et al, 2011), and a recent study shows that the Mos-MAPK pathway triggers Arp2/3 activity during spindle movement to the cortex (Chaigne et al, 2013), thus regulation of Arp2/3 during PBE by the Mos-MAPK pathway is also possible. Since regulation of Arp2/3 and Dia might involve Cdc42 and RhoA, respectively, it would be interesting to examine whether active RhoA and active Cdc42 localizations during PBE are regulated by the Mos-MAPK pathway.…”

Section: Discussionmentioning

confidence: 99%

The Mos-MAPK pathway regulates Diaphanous-related formin activity to drive cleavage furrow closure during polar body emission in starfish oocytes

Ucar

Tachibana

Kishimoto

2013

Journal of Cell Science

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SummaryMaintenance of spindle attachment to the cortex and formation of the cleavage furrow around the protruded spindle are essential for polar body extrusion (PBE) during meiotic maturation of oocytes. Although spindle movement to the cortex has been well-studied, how the spindle is maintained at the cortex during PBE is unknown. Here, we show that activation of Diaphanous-related formin mediated by mitogen-activated protein kinase (MAPK) is required for tight spindle attachment to the cortex and cleavage furrow closure during PBE in starfish (Asterina pectinifera) oocytes. A. pectinifera Diaphanous-related formin (ApDia) had a distinct localization in immature oocytes and was localized to the cleavage furrow during PBE. Inhibition of the Mos-MAPK pathway or the actin nucleating activity of formin homology 2 domain prevented cleavage furrow closure and resulted in PBE failure. In MEK/MAPK-inhibited oocytes, activation of ApDia by relief of its intramolecular inhibition restored PBE. In summary, this study elucidates a link between the Mos-MAPK pathway and Diaphanous-related formins, that is responsible for maintaining tight spindle attachment to the cortex and cleavage furrow closure during PBE.

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“…Although these experiments clearly showed that the phosphorylation of Abi1 Ser-216 is increased at the onset of mitosis, they could not exclude the possibility that a basal phosphorylation of Ser-216 may also occur in interphase cells at a level too low to be detected by our antibody. Indeed, using a combination of affinity purification and mass spectrometry analysis, the phosphorylation of serine 216 in Abi1 has been identified in both serumstarved and EGF-stimulated A-431 cells and possibly other cells as well (15,19), suggesting its basal phosphorylation in interphase cells.…”

Section: Discussionmentioning

confidence: 99%

CDK1-mediated Phosphorylation of Abi1 Attenuates Bcr-Abl-induced F-actin Assembly and Tyrosine Phosphorylation of WAVE Complex during Mitosis

Zhuang

Tang

Cobos

et al. 2011

Journal of Biological Chemistry

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Coordinated actin remodeling is crucial for cell entry into mitosis. The WAVE regulatory complex is a key regulator of actin assembly, yet how the WAVE signaling is regulated to coordinate actin assembly with mitotic entry is not clear. Here, we have uncovered a novel mechanism that regulates the WAVE complex at the onset of mitosis. We found that the Bcr-Ablstimulated F-actin assembly is abrogated during mitosis. This mitotic inhibition of F-actin assembly is accompanied by an attenuation of Bcr-Abl-induced tyrosine phosphorylation of the WAVE complex. We identified serine 216 of Abi1 as a target of CDK1/cyclin B kinase that is phosphorylated in cells at the onset of mitosis. The Abi1 phosphorylated on serine 216 displayed greatly reduced tyrosine phosphorylation in the hematopoietic cells transformed by Bcr-Abl. Moreover, a phosphomimetic mutation of serine 216 to aspartic acid in Abi1 was sufficient to attenuate Bcr-Abl-induced tyrosine phosphorylation of the WAVE complex and F-actin assembly. Ectopic expression of Abi1 with serine 216 mutations interfered with cell cycle progression. Together, these data show that CDK1-mediated phosphorylation of serine 216 in Abi1 serves as a regulatory mechanism that may contribute to coordinated actin cytoskeleton remodeling during mitosis.Actin cytoskeleton remodeling is a dynamic process that regulates many fundamental cellular functions such as cell adhesion, division, intracellular trafficking, morphogenesis, and motility (1, 2). This cellular process is regulated spatiotemporally not only by extracellular signals such as growth factors, chemoattractants, and extracellular matrix but also by intracellular signals that control cell cycle progression (2-4). Tight regulation by both extracellular and intracellular signals ensures that proper cytoskeleton rearrangement is achieved and coordinated with a broad range of cellular functions including directional movement and cell division.

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ERK-MAPK Drives Lamellipodia Protrusion by Activating the WAVE2 Regulatory Complex

Cited by 153 publications

References 51 publications

Gab2 Phosphorylation by RSK Inhibits Shp2 Recruitment and Cell Motility

Gab2 Phosphorylation by RSK Inhibits Shp2 Recruitment and Cell Motility

The Mos-MAPK pathway regulates Diaphanous-related formin activity to drive cleavage furrow closure during polar body emission in starfish oocytes

CDK1-mediated Phosphorylation of Abi1 Attenuates Bcr-Abl-induced F-actin Assembly and Tyrosine Phosphorylation of WAVE Complex during Mitosis

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