SH3P2 is a negative regulator of cell motility whose function is inhibited by ribosomal S6 kinase-mediated phosphorylation

Tanimura, Susumu; Hashizume, Junya; Kurosaki, Yukiko; Sei, Kanako; Gotoh, Aiko; Ohtake, Rika; Kawano, Mitsuko; Watanabe, Kazushi; Kohno, Michiaki

doi:10.1111/j.1365-2443.2011.01503.x

Cited by 25 publications

(30 citation statements)

References 34 publications

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“…41). RSK phosphorylation promoted cell motility by inhibiting the activity of SH3P2 (41). Our data indicate a role for regulation of the closely situated S213 by a CK2 family kinase.…”

Section: Discussionmentioning

confidence: 73%

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Phosphoproteomics of MAPK Inhibition in BRAF-Mutated Cells and a Role for the Lethal Synergism of Dual BRAF and CK2 Inhibition

Parker

Clifton‐Bligh

Molloy

2014

Molecular Cancer Therapeutics

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Activating mutations in the MAPK pathway are prevalent drivers of several cancers. The chief consequence of these mutations is a hyperactive ERK1/2 MAPK able to promote cell proliferation, producing a critical hallmark of metastatic disease. The biochemistry of the ERK pathway is well characterized; however, how the pathway achieves different outcomes in the face of genetic aberrations of cancer and subsequent treatment with chemical inhibitors is not clear. To investigate this, we used mass spectrometry to complete a global phosphoproteomic analysis of a BRAFV600E thyroid cancer cell line (SW1736) after treatment with the mutation-selective inhibitor vemurafenib (PLX4032) and MEK1/2 inhibitor selumetinib (AZD6244). We identified thousands of phosphorylation events orchestrated in BRAFV600E cells and performed kinase landscape analysis to identify putative kinases regulated in response to MAPK blockade. The abundance of phosphopeptides containing consensus motifs for acidophilic kinases increased after short-term inhibition with these compounds. We showed that coinhibition of the pleiotropic acidophilic protein kinase CK2 (CK2) and BRAFV600E synergistically reduced proliferation in patient-derived melanomas and thyroid cancer cells harboring the BRAF lesion. We investigated this mechanism and show a role for CK2 in controlling AKT activation that was not reliant on changes to PTEN or PDK1 phosphorylation. These findings highlight a role for CK2 blockade in potentiating the antiproliferative effects of BRAF and MEK inhibition in BRAF cancers. Mol Cancer Ther; 13(7); 1894-906. Ó2014 AACR.

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“…41). RSK phosphorylation promoted cell motility by inhibiting the activity of SH3P2 (41). Our data indicate a role for regulation of the closely situated S213 by a CK2 family kinase.…”

Section: Discussionmentioning

confidence: 73%

“…Recently, phosphorylation of SH3P2 at S202 was shown to be ERK dependent and catalyzed by ribosome S6 kinase (RSK; ref. 41). RSK phosphorylation promoted cell motility by inhibiting the activity of SH3P2 (41).…”

Section: Discussionmentioning

confidence: 99%

Phosphoproteomics of MAPK Inhibition in BRAF-Mutated Cells and a Role for the Lethal Synergism of Dual BRAF and CK2 Inhibition

Parker

Clifton‐Bligh

Molloy

2014

Molecular Cancer Therapeutics

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“…In addition, BI-D1870 decreased invadopodia formation of fibrosarcoma cells under hypoxic conditions (3). Inhibitor treatment increased the level of cell adhesion after EGF stimulation in carcinoma cells and blocked cell migration in gastric and bladder cancers (15, 27). These studies show that a drug lead does not have to be specific for only one RSK isoform in order to be effective in blocking cancer cell motility.…”

Section: Targeting Invasion and Metastasis By Inhibiting Rsk Isoformsmentioning

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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“…The family of RSKs is involved in various cellular processes such as translation, apoptosis, and phagocytosis, and regulates cell proliferation, growth, and motility. 21,22 Following activation by the extracellular signal regulated kinase 1/2 (ERK1/2) signaling cascade, they, among others, phosphorylate transcription factors such as cAMP response element binding protein (CREB) and serum response factor (SRF). 23 YopM has been described to induce hyperactivation of RSK by inhibiting the dephosphorylation of serine 380 (S380).…”

Section: Ryopm Enhances Autophosphorylation Of Rsk After Autonomous Tmentioning

confidence: 99%

Manipulation of pro-inflammatory cytokine production by the bacterial cell-penetrating effector protein YopM is independent of its interaction with host cell kinases RSK1 and PRK2

et al. 2014

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The effector protein Yersinia outer protein M (YopM) of Yersinia enterocolitica has previously been identified and characterized as the first bacterial cell-penetrating protein (CPP). We found that recombinant YopM (rYopM) enters different eukaryotic cell types and downregulates the expression of several pro-inflammatory cytokines (e.g., tumor necrosis factor-α [TNF-α]) after autonomous translocation. After infection with Y. enterocolitica or transfection of host cells, YopM interacts with isoforms of the two kinases ribosomal S6 protein kinase (RSK) and protein kinase C-related kinase (PRK). This interaction caused sustained RSK activation due to interference with dephosphorylation. Here we demonstrate by co-immunoprecipitation that rYopM interacts with RSK and PRK following cell-penetration. We show that autonomously translocated rYopM forms a trimeric complex with different RSK and PRK isoforms. Furthermore, we constructed a series of truncated versions of rYopM to map the domain required for the formation of the complex. The C-terminus of rYopM was identified to be essential for the interaction with RSK1, whereas any deletion in rYopM's leucin-rich repeat domains abrogated PRK2 binding. Moreover, we found that the interaction of cell-penetrating rYopM with RSK led to enhanced autophosphorylation of this kinase at serine 380. Finally, we investigated whether downstream signaling of the trimeric rYopM-RSK/PRK complex modulates the expression of pro-inflammatory TNF-α. Here, we could exclude that interaction with RSK1 and PRK2 is essential for the anti-inflammatory effects of rYopM.

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SH3P2 is a negative regulator of cell motility whose function is inhibited by ribosomal S6 kinase-mediated phosphorylation

Cited by 25 publications

References 34 publications

Phosphoproteomics of MAPK Inhibition in BRAF-Mutated Cells and a Role for the Lethal Synergism of Dual BRAF and CK2 Inhibition

Phosphoproteomics of MAPK Inhibition in BRAF-Mutated Cells and a Role for the Lethal Synergism of Dual BRAF and CK2 Inhibition

RSK Isoforms in Cancer Cell Invasion and Metastasis

Manipulation of pro-inflammatory cytokine production by the bacterial cell-penetrating effector protein YopM is independent of its interaction with host cell kinases RSK1 and PRK2

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