Epidermal Growth Factor (EGF) Regulates α5β1 Integrin Activation State in Human Cancer Cell Lines through the p90RSK-dependent Phosphorylation of Filamin A

Vial, Daniel; McKeown‐Longo, Paula J.

doi:10.1074/jbc.m112.389577

Cited by 34 publications

(35 citation statements)

References 33 publications

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“…RSK-dependent regulation of integrin activity occurs by ERK-dependent and independent mechanisms (Gawecka et al, 2012;Vial and McKeown-Longo, 2012). We found that the inhibition of either ERK or RSK led to a similar phenotype in CHO cells, which suggests that ERK and RSK are functioning together in the same pathway in these cells.…”

Section: Discussionmentioning

confidence: 58%

“…Interestingly, RSK has been shown to suppress integrin activity by phosphorylating filamin A (Gawecka et al, 2012;Vial and McKeown-Longo, 2012). It has been proposed that RSK2 functions in a feedback loop to modulate integrin activity during cell migration with integrins activating RSK, which feeds back to negatively regulate integrin activity (Gawecka et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

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Integrins Promote Cytokinesis through the RSK Signaling Axis

Mathew

Nieves

Sequeira

et al. 2013

Journal of Cell Science

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Cytokinesis is the final stage in cell division. Although integrins can regulate cytokinesis, the mechanisms involved are not fully understood. In this study, we demonstrate that integrin-regulated ERK (extracellular signal-related kinase) and RSK (p90 ribosomal S6 kinase) signaling promotes successful cytokinesis. Inhibiting the activation of ERK and RSK in CHO cells by a mutation in the integrin b1 cytoplasmic tail or with pharmacological inhibitors results in the accumulation of cells with midbodies and the formation of binucleated cells. Activation of ERK and RSK signaling by the expression of constitutively active RAF1 suppresses the mutant phenotype in a RSK-dependent manner. Constitutively active RSK2 also restores cytokinesis inhibited by the mutant integrin. Importantly, the regulatory role of the RSK pathway is not specific to CHO cells. MCF-10A human mammary epithelial cells and HPNE human pancreatic ductal epithelial cells exhibit a similar dependence on RSK for successful cytokinesis. In addition, depriving mitotic MCF10A cells of integrin-mediated adhesion by incubating them in suspension suppressed ERK and RSK activation and resulted in a failure of cytokinesis. Furthermore, inhibition of RSK or integrins within the 3D context of a developing salivary gland organ explant also leads to an accumulation of epithelial cells with midbodies, suggesting a similar defect in cytokinesis. Interestingly, neither ERK nor RSK regulates cytokinesis in human fibroblasts, suggesting cell-type specificity. Taken together, our results identify the integrin-RSK signaling axis as an important regulator of cytokinesis in epithelial cells. We propose that the proper interaction of cells with their microenvironment through integrins contributes to the maintenance of genomic stability by promoting the successful completion of cytokinesis.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Integrins Promote Cytokinesis through the RSK Signaling Axis

Mathew

Nieves

Sequeira

et al. 2013

Journal of Cell Science

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“…Whether RSK2 prevents formation of the focal adhesion complex or promotes its dissolution or both was left unresolved. An independent study similarly found that RSK inhibition blocked integrin-mediated cell adhesion and proposed that RSKs regulate α5β1 integrin activation in colon cancer and human squamous carcinoma cells through FLNa phosphorylation (15). The study did not differentiate between different RSK isoforms.…”

Section: Rsk Isoforms Regulate Cell Adhesionmentioning

confidence: 99%

RSK Isoforms in Cancer Cell Invasion and Metastasis

2013

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Metastasis, the spreading of cancer cells from a primary tumor to secondary sites throughout the body, is the primary cause of death for cancer patients. New therapies that prevent invasion and metastasis in combination with current treatments could therefore significantly reduce cancer recurrence and morbidity. Metastasis is driven by altered signaling pathways that induce changes in cell-cell adhesion, the cytoskeleton, integrin function, protease expression, epithelial to mesenchymal transition and cell survival. The RSK family of kinases is a group of ERK/MAPK effectors that can regulate these steps of metastasis by phosphorylating both nuclear and cytoplasmic targets. However, our understanding of RSK function in metastasis remains incomplete and is complicated by the fact that the four RSK isoforms perform non-redundant, sometimes opposing functions. While some isoforms promote cell motility and invasion by altering transcription and integrin activity, others impair cell motility and invasion through effects on the actin cytoskeleton. The mechanism of RSK action depends both on the isoform and the cancer type. However, despite the variance in RSK-mediated outcomes, chemical inhibition of this group of kinases has proven effective in blocking invasion and metastasis of several solid tumors in pre-clinical models. RSKs are therefore a promising drug target for anti-metastatic cancer treatments that could supplement and improve current therapeutic approaches. This review highlights contradiction and agreement in the current data on the function of RSK isoforms in metastasis and suggests ways forward in developing RSK inhibitors as new anti-metastasis drugs.

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“…6B). Recently, cell rounding induced by epidermal growth factor (EGF) has been linked to EGF receptor (EGFR)-mediated integrin inactivation and phosphorylation of filamin A, a well-established inhibitor of integrin activity (Vial and McKeown-Longo, 2012). This mechanism might be generally involved in cell rounding that is induced by receptor tyrosine kinases, because we also observed increased filamin A phosphorylation upon c-Met induction (Fig.…”

Section: C-met Overexpression Induces Filamin a Phosphorylation And Amentioning

confidence: 51%

Distinct c-Met activation mechanisms induce cell rounding or invasion through pathways involving integrins, RhoA and HIP1

Mai

Muharram

Barrow-McGee

et al. 2014

Journal of Cell Science

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Many carcinomas have acquired oncogenic mechanisms for activating c-Met, including c-Met overexpression and excessive autocrine or paracrine stimulation with hepatocyte growth factor (HGF). However, the biological outcome of c-Met activation through these distinct modes remains ambiguous. Here, we report that HGF-mediated c-Met stimulation triggers a mesenchymal-type collective cell invasion. By contrast, the overexpression of c-Met promotes cell rounding. Moreover, in a high-throughput siRNA screen that was performed using a library of siRNAs against putative regulators of integrin activity, we identified RhoA and the clathrin-adapter protein HIP1 as crucial c-Met effectors in these morphological changes. Transient RhoA activation was necessary for the HGF-induced invasion, whereas sustained RhoA activity regulated c-Met-induced cell rounding. In addition, c-Met-induced cell rounding correlated with the phosphorylation of filamin A and the downregulation of active cell-surface integrins. By contrast, a HIP1-mediated increase in β1-integrin turnover was required for the invasion triggered by HGF. Taken together, our results indicate that c-Met induces distinct cell morphology alterations depending on the stimulus that activates c-Met.

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Epidermal Growth Factor (EGF) Regulates α5β1 Integrin Activation State in Human Cancer Cell Lines through the p90RSK-dependent Phosphorylation of Filamin A

Cited by 34 publications

References 33 publications

Integrins Promote Cytokinesis through the RSK Signaling Axis

Integrins Promote Cytokinesis through the RSK Signaling Axis

RSK Isoforms in Cancer Cell Invasion and Metastasis

Distinct c-Met activation mechanisms induce cell rounding or invasion through pathways involving integrins, RhoA and HIP1

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