Philippe P Roux | Université de Montréal (original) (raw)

Papers by Philippe P Roux

Research paper thumbnail of RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation

Biochemical Journal, 2012

The extent and duration of MAPK (mitogen-activated protein kinase) signalling govern a diversity ... more The extent and duration of MAPK (mitogen-activated protein kinase) signalling govern a diversity of normal and aberrant cellular outcomes. Genetic and pharmacological disruption of the MAPK-activated kinase RSK (ribosomal S6 kinase) leads to elevated MAPK activity indicative of a RSK-dependent negative feedback loop. Using biochemical, pharmacological and quantitative MS approaches we show that RSK phosphorylates the Ras activator SOS1 (Son of Sevenless homologue 1) in cultured cells on two C-terminal residues, Ser(1134) and Ser(1161). Furthermore, we find that RSK-dependent SOS1 phosphorylation creates 14-3-3-binding sites. We show that mutating Ser(1134) and Ser(1161) disrupts 14-3-3 binding and modestly increases and extends MAPK activation. Together these data suggest that one mechanism whereby RSK negatively regulates MAPK activation is via site-specific SOS1 phosphorylation.

Research paper thumbnail of ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions

Microbiology and Molecular Biology Reviews, 2004

Research paper thumbnail of 4E-T phosphorylation by JNK promotes stress-dependent P-body assembly

Processing bodies (PBs, or P bodies) are cytoplasmic granules involved in mRNA storage and degrad... more Processing bodies (PBs, or P bodies) are cytoplasmic granules involved in mRNA storage and degradation that participate in the regulation of gene expression. PBs concentrate nontranslated mRNAs and several factors involved in mRNA decay and translational repression, including the eukaryotic translation initiation factor 4E-transporter (4E-T). 4E-T is required for PB assembly, but little is known about the molecular mechanisms that regulate its function. Here, we demonstrate that oxidative stress promotes multisite 4E-T phosphorylation. We show that the c-Jun N-terminal kinase (JNK) is targeted to PBs in response to oxidative stress and promotes the phosphorylation of 4E-T. Quantitative mass spectrometry analysis reveals that JNK phosphorylates 4E-T on six proline-directed sites that are required for the formation of the 4E-T complex upon stress. We have developed an image-based computational method to quantify the size, number, and density of PBs in cells, and we find that while 4E-T is required for steady-state PB assembly, its phosphorylation facilitates the formation of larger PBs upon oxidative stress. Using polysomal mRNA profiling, we assessed global and specific mRNA translation but did not find that 4E-T phosphorylation impacts translational control. Collectively, these data support a model whereby PB assembly is regulated by a two-step mechanism involving a 4E-T-dependent assembly stage in unstressed cells and a 4E-T phosphorylation-dependent aggregation stage in response to stress stimuli.

Research paper thumbnail of Mind the GAP: Wnt Steps onto the mTORC1 Train

Research paper thumbnail of Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase

Proceedings of the National Academy of Sciences of the United States of America, Jan 14, 2004

Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in either of the two t... more Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in either of the two tumor suppressor genes TSC1 or TSC2, which encode hamartin and tuberin, respectively. Tuberin and hamartin form a complex that inhibits signaling by the mammalian target of rapamycin (mTOR), a critical nutrient sensor and regulator of cell growth and proliferation. Phosphatidylinositol 3-kinase (PI3K) inactivates the tumor suppressor complex and enhances mTOR signaling by means of phosphorylation of tuberin by Akt. Importantly, cellular transformation mediated by phorbol esters and Ras isoforms that poorly activate PI3K promote tumorigenesis in the absence of Akt activation. In this study, we show that phorbol esters and activated Ras also induce the phosphorylation of tuberin and collaborates with the nutrient-sensing pathway to regulate mTOR effectors, such as p70 ribosomal S6 kinase 1 (S6K1). The mitogen-activated protein kinase (MAPK)-activated kinase, p90 ribosomal S6 kinase (RSK) 1,...

Research paper thumbnail of MAPK signaling in human diseases

... 13. Gonzalez FA, Seth A, Raden DL, Bowman DS, Fay FS, Davis RJ. Serum-induced translocation o... more ... 13. Gonzalez FA, Seth A, Raden DL, Bowman DS, Fay FS, Davis RJ. Serum-induced translocation of mitogen-activated protein kinase to the cell surface ruffling membrane and the nucleus. ... Cell 1994;76:1025–1037. 92. Gupta S, Barrett T, Whitmarsh AJ, et al. ...

Research paper thumbnail of Y-box binding protein-1 (YB-1) serine 102 is a downstream target of p90 ribosomal S6 kinase in breast cancer cells

Introduction Basal-like breast cancers (BLBC) frequently overexpress the epidermal growth factor ... more Introduction Basal-like breast cancers (BLBC) frequently overexpress the epidermal growth factor receptor (EGFR) and subsequently have high levels of signaling through the MAP kinase pathway, which is thought to contribute to their aggressive behavior. While we have previously reported the expression of Y-box binding protein-1 (YB-1) in 73% of BLBC, it is unclear whether it can be regulated by a component of the MAP kinase signaling pathway. Phosphorylation of YB-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as EGFR. Using Motifscan we identified p90 ribosomal S6 kinase (RSK) as a potential candidate for activating YB-1.

Research paper thumbnail of Gene Section

Research paper thumbnail of RSK (p90 Ribosomal S6 Kinase)

Research paper thumbnail of Regulation of global and specific mRNA translation by the mTOR signaling pathway

ABSTRACT The translation of mRNA into polypeptides is a key step in eukaryotic gene expression. T... more ABSTRACT The translation of mRNA into polypeptides is a key step in eukaryotic gene expression. Translation is mostly controlled at the level of initiation, which is partly regulated by the mammalian/mechanistic target of rapamycin (mTOR) signaling pathway. Whereas mTOR controls global protein synthesis through specific effector proteins, its role in the translation of select groups of mRNAs, such as those harboring a terminal oligopyrimidine (TOP) tract at their 5’ end, remains more enigmatic. In this article, we describe the current knowledge on the role of mTOR in global mRNA translation, but also focus on the potential molecular mechanisms underlying the regulation of specific translational programs.

Research paper thumbnail of Signaling pathways implicated in p75 neurotrophin receptor-mediated neuronal survival and death

Research paper thumbnail of INCREASED APOPTOSIS, CHANGES IN INTRACELLULAR Ca2+, AND FUNCTIONAL ALTERATIONS IN LYMPHOCYTES AND MACROPHAGES AFTER IN VITRO EXPOSURE TO STATIC MAGNETIC FIELD

Journal of Toxicology and Environmental Health, Part A, 1998

Research paper thumbnail of Regulation and function of the RSK family of protein kinases

Biochemical Journal, 2012

The RSK (90 kDa ribosomal S6 kinase) family comprises a group of highly related serine/threonine ... more The RSK (90 kDa ribosomal S6 kinase) family comprises a group of highly related serine/threonine kinases that regulate diverse cellular processes, including cell growth, proliferation, survival and motility. This family includes four vertebrate isoforms (RSK1, RSK2, RSK3 and RSK4), and single family member orthologues are also present in Drosophila and Caenorhabditis elegans. The RSK isoforms are downstream effectors of the Ras/ERK (extracellular-signal-regulated kinase) signalling pathway. Significant advances in the field of RSK signalling have occurred in the past few years, including several new functions ascribed to the RSK isoforms, the discovery of novel protein substrates and the implication of different RSK isoforms in cancer. Collectively, these new findings increase the diversity of biological functions regulated by RSK, and highlight potential new directions of research. In the present paper, we review the structure, expression and activation mechanisms of the RSK isoforms, and discuss their physiological roles on the basis of established substrates and recent discoveries. initiation factor; 4E-BP1, eIF4E-binding protein 1; Emi, early mitotic inhibitor; ERα, oestrogen receptor α; ERK, extracellular-signal-regulated kinase; Erp1, Emi1-related protein; EST, expressed sequence tag; ETS, E twenty-six; Elk1, ETS-like kinase 1; FGFR3, fibroblast growth factor receptor 3; FMK, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone; GLUT4, glucose transporter 4; GSK3, glycogen synthase kinase-3; IκB, inhibitor of nuclear factor κB; IEG, immediate-early gene; IFN, interferon; KIM, kinase interaction motif; LKB1, liver kinase B1; Mad, mitotic arrest-deficient protein; MAP, microtuble-associated protein; MAPK, mitogen-activated protein kinase; MDCK cell, Madin-Darby canine kidney cell; MEK, MAPK/ERK kinase; MK, MAPK-activated protein kinase; MSK, mitogen-and stress-activated kinase; mTOR, mammalian target of rapamycin; Myt1, myelin transcription factor 1; NF-κB, nuclear factor κB; NOS, nitric oxide synthase; nNOS, neuronal NOS; NTKD, N-terminal kinase domain; p27 kip1 , cyclin-dependent kinase inhibitor 1B; PAK1, p21-activated kinase-1; PDK1, 3 -phosphoinositide-dependent protein kinase 1; PEA-15, phosphoprotein enriched in astrocytes, 15 kDa; PIF, PDK1-interacting fragment; PKA, protein kinase A; RanBP3, Ran-binding protein 3; RNAi, RNA interference; rpS6, ribosomal protein S6; RSK, 90 kDa ribosomal S6 kinase; S6K, S6 kinase; SGK, serum-and glucocorticoid-induced protein kinase; SOS, son of sevenless; SRF, serum-response factor; TSC2, tuberous sclerosis complex 2; YB-1, Y-box binding protein-1.

Research paper thumbnail of Cell Growth Regulation by PI3-kinase, Ras and mTOR Signal Integration

Research paper thumbnail of The expanding role of mTOR in cancer cell growth and proliferation

Mutagenesis, 2015

The mechanistic/mammalian target of rapamycin (mTOR) is a conserved protein kinase that controls ... more The mechanistic/mammalian target of rapamycin (mTOR) is a conserved protein kinase that controls several anabolic processes required for cell growth and proliferation. As such, mTOR has been implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes and neurodegeneration. As part of the mTOR complex 1 (mTORC1), mTOR regulates cell growth by promoting the biosynthesis of proteins, lipids and nucleic acids. Several mTORC1 substrates have been shown to regulate protein synthesis, including the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs) and the ribosomal S6 kinases (S6Ks) 1 and 2. In this work, we focus on the signalling pathways that lie both upstream and downstream of mTORC1, as well as their relevance to human pathologies. We further discuss pharmacological approaches that target mTOR and their applications for the treatment of cancer.

Research paper thumbnail of Translational control by oncogenic signaling pathways

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 2014

Research paper thumbnail of Rapamycin Resistance: mTORC1 Substrates Hold Some of the Answers

Current Biology, 2013

2010). Where's the glass? Biomarkers, molecular clocks, and microRNAs suggest a 200-Myr missing P... more 2010). Where's the glass? Biomarkers, molecular clocks, and microRNAs suggest a 200-Myr missing Precambrian fossil record of siliceous sponge spicules. Geobiology 8, 24-36. 9. Antcliffe, J., Callow, R., and Brasier, M. (2013).

Research paper thumbnail of Insulin Activates RSK (p90 Ribosomal S6 Kinase) to Trigger a New Negative Feedback Loop That Regulates Insulin Signaling for Glucose Metabolism

Journal of Biological Chemistry, 2013

Background: RSK is a downstream effector of the Ras/ERK pathway and shares high homology with S6K... more Background: RSK is a downstream effector of the Ras/ERK pathway and shares high homology with S6K. Results: RSK1 inhibition improved insulin signaling and insulin action on glucose metabolism in myotubes and hepatocytes by preventing IRS-1 Ser-1101 phosphorylation. Conclusion: RSK1 promotes insulin resistance by phosphorylating IRS-1 Ser-1101. Significance: RSK1 might be a new mediator of insulin resistance in hyperinsulinemia or diabetic states. The abbreviations used are: IRG, insulin receptor substrate; 2-DG, 2-deoxyglucose; AA, amino acid; RSK, p90 ribosomal S6 kinase; mTOR, mammalian target of rapamycin; S6K1, p70 S6 kinase; CTKD, C-terminal kinase domains; NTKD, N-terminal kinase domains.

Research paper thumbnail of Phosphoproteomic analysis identifies the tumor suppressor PDCD4 as a RSK substrate negatively regulated by 14-3-3

Proceedings of the National Academy of Sciences of the United States of America, Jan 22, 2014

The Ras/MAPK signaling cascade regulates various biological functions, including cell growth and ... more The Ras/MAPK signaling cascade regulates various biological functions, including cell growth and proliferation. As such, this pathway is frequently deregulated in several types of cancer, including most cases of melanoma. RSK (p90 ribosomal S6 kinase) is a MAPK-activated protein kinase required for melanoma growth and proliferation, but relatively little is known about its exact function and the nature of its substrates. Herein, we used a quantitative phosphoproteomics approach to define the signaling networks regulated by RSK in melanoma. To more accurately predict direct phosphorylation substrates, we defined the RSK consensus phosphorylation motif and found significant overlap with the binding consensus of 14-3-3 proteins. We thus characterized the phospho-dependent 14-3-3 interactome in melanoma cells and found that a large proportion of 14-3-3 binding proteins are also potential RSK substrates. Our results show that RSK phosphorylates the tumor suppressor PDCD4 (programmed cell...

Research paper thumbnail of Casein Kinase 1  Promotes Cell Proliferation by Regulating mRNA Translation

Cancer Research, 2014

Deregulation of translation initiation factors contributes to many pathogenic conditions, includi... more Deregulation of translation initiation factors contributes to many pathogenic conditions, including cancer. Here, we report the definition of a novel regulatory pathway for translational initiation with possible therapeutic import in cancer. Specifically, we found that casein kinase 1e (CK1e) is highly expressed in breast tumors and plays a critical role in cancer cell proliferation by controlling mRNA translation. Eukaryotic translation initiation factor eIF4E, an essential component of the translation initiation complex eIF4F, is downregulated by binding the negative-acting factor 4E-BP1. We found that genetic or pharmacologic inhibition of CK1e attenuated 4E-BP1 phosphorylation, thereby increasing 4E-BP1 binding to eIF4E and inhibiting mRNA translation. Mechanistic investigations showed that CK1e interacted with and phosphorylated 4E-BP1 at two novel sites T41 and T50, which were essential for 4E-BP1 inactivation along with increased mRNA translation and cell proliferation. In summary, our work identified CK1e as a pivotal regulator of mRNA translation and cell proliferation that acts by inhibiting 4E-BP1 function. As CK1e is highly expressed in breast tumors, these findings offer an initial rationale to explore CK1e blockade as a therapeutic strategy to treat cancers driven by deregulated mRNA translation. Cancer Res; 74(1); 201-11. Ó2013 AACR.

Research paper thumbnail of RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation

Biochemical Journal, 2012

The extent and duration of MAPK (mitogen-activated protein kinase) signalling govern a diversity ... more The extent and duration of MAPK (mitogen-activated protein kinase) signalling govern a diversity of normal and aberrant cellular outcomes. Genetic and pharmacological disruption of the MAPK-activated kinase RSK (ribosomal S6 kinase) leads to elevated MAPK activity indicative of a RSK-dependent negative feedback loop. Using biochemical, pharmacological and quantitative MS approaches we show that RSK phosphorylates the Ras activator SOS1 (Son of Sevenless homologue 1) in cultured cells on two C-terminal residues, Ser(1134) and Ser(1161). Furthermore, we find that RSK-dependent SOS1 phosphorylation creates 14-3-3-binding sites. We show that mutating Ser(1134) and Ser(1161) disrupts 14-3-3 binding and modestly increases and extends MAPK activation. Together these data suggest that one mechanism whereby RSK negatively regulates MAPK activation is via site-specific SOS1 phosphorylation.

Research paper thumbnail of ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions

Microbiology and Molecular Biology Reviews, 2004

Research paper thumbnail of 4E-T phosphorylation by JNK promotes stress-dependent P-body assembly

Processing bodies (PBs, or P bodies) are cytoplasmic granules involved in mRNA storage and degrad... more Processing bodies (PBs, or P bodies) are cytoplasmic granules involved in mRNA storage and degradation that participate in the regulation of gene expression. PBs concentrate nontranslated mRNAs and several factors involved in mRNA decay and translational repression, including the eukaryotic translation initiation factor 4E-transporter (4E-T). 4E-T is required for PB assembly, but little is known about the molecular mechanisms that regulate its function. Here, we demonstrate that oxidative stress promotes multisite 4E-T phosphorylation. We show that the c-Jun N-terminal kinase (JNK) is targeted to PBs in response to oxidative stress and promotes the phosphorylation of 4E-T. Quantitative mass spectrometry analysis reveals that JNK phosphorylates 4E-T on six proline-directed sites that are required for the formation of the 4E-T complex upon stress. We have developed an image-based computational method to quantify the size, number, and density of PBs in cells, and we find that while 4E-T is required for steady-state PB assembly, its phosphorylation facilitates the formation of larger PBs upon oxidative stress. Using polysomal mRNA profiling, we assessed global and specific mRNA translation but did not find that 4E-T phosphorylation impacts translational control. Collectively, these data support a model whereby PB assembly is regulated by a two-step mechanism involving a 4E-T-dependent assembly stage in unstressed cells and a 4E-T phosphorylation-dependent aggregation stage in response to stress stimuli.

Research paper thumbnail of Mind the GAP: Wnt Steps onto the mTORC1 Train

Research paper thumbnail of Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase

Proceedings of the National Academy of Sciences of the United States of America, Jan 14, 2004

Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in either of the two t... more Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in either of the two tumor suppressor genes TSC1 or TSC2, which encode hamartin and tuberin, respectively. Tuberin and hamartin form a complex that inhibits signaling by the mammalian target of rapamycin (mTOR), a critical nutrient sensor and regulator of cell growth and proliferation. Phosphatidylinositol 3-kinase (PI3K) inactivates the tumor suppressor complex and enhances mTOR signaling by means of phosphorylation of tuberin by Akt. Importantly, cellular transformation mediated by phorbol esters and Ras isoforms that poorly activate PI3K promote tumorigenesis in the absence of Akt activation. In this study, we show that phorbol esters and activated Ras also induce the phosphorylation of tuberin and collaborates with the nutrient-sensing pathway to regulate mTOR effectors, such as p70 ribosomal S6 kinase 1 (S6K1). The mitogen-activated protein kinase (MAPK)-activated kinase, p90 ribosomal S6 kinase (RSK) 1,...

Research paper thumbnail of MAPK signaling in human diseases

... 13. Gonzalez FA, Seth A, Raden DL, Bowman DS, Fay FS, Davis RJ. Serum-induced translocation o... more ... 13. Gonzalez FA, Seth A, Raden DL, Bowman DS, Fay FS, Davis RJ. Serum-induced translocation of mitogen-activated protein kinase to the cell surface ruffling membrane and the nucleus. ... Cell 1994;76:1025–1037. 92. Gupta S, Barrett T, Whitmarsh AJ, et al. ...

Research paper thumbnail of Y-box binding protein-1 (YB-1) serine 102 is a downstream target of p90 ribosomal S6 kinase in breast cancer cells

Introduction Basal-like breast cancers (BLBC) frequently overexpress the epidermal growth factor ... more Introduction Basal-like breast cancers (BLBC) frequently overexpress the epidermal growth factor receptor (EGFR) and subsequently have high levels of signaling through the MAP kinase pathway, which is thought to contribute to their aggressive behavior. While we have previously reported the expression of Y-box binding protein-1 (YB-1) in 73% of BLBC, it is unclear whether it can be regulated by a component of the MAP kinase signaling pathway. Phosphorylation of YB-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as EGFR. Using Motifscan we identified p90 ribosomal S6 kinase (RSK) as a potential candidate for activating YB-1.

Research paper thumbnail of Gene Section

Research paper thumbnail of RSK (p90 Ribosomal S6 Kinase)

Research paper thumbnail of Regulation of global and specific mRNA translation by the mTOR signaling pathway

ABSTRACT The translation of mRNA into polypeptides is a key step in eukaryotic gene expression. T... more ABSTRACT The translation of mRNA into polypeptides is a key step in eukaryotic gene expression. Translation is mostly controlled at the level of initiation, which is partly regulated by the mammalian/mechanistic target of rapamycin (mTOR) signaling pathway. Whereas mTOR controls global protein synthesis through specific effector proteins, its role in the translation of select groups of mRNAs, such as those harboring a terminal oligopyrimidine (TOP) tract at their 5’ end, remains more enigmatic. In this article, we describe the current knowledge on the role of mTOR in global mRNA translation, but also focus on the potential molecular mechanisms underlying the regulation of specific translational programs.

Research paper thumbnail of Signaling pathways implicated in p75 neurotrophin receptor-mediated neuronal survival and death

Research paper thumbnail of INCREASED APOPTOSIS, CHANGES IN INTRACELLULAR Ca2+, AND FUNCTIONAL ALTERATIONS IN LYMPHOCYTES AND MACROPHAGES AFTER IN VITRO EXPOSURE TO STATIC MAGNETIC FIELD

Journal of Toxicology and Environmental Health, Part A, 1998

Research paper thumbnail of Regulation and function of the RSK family of protein kinases

Biochemical Journal, 2012

The RSK (90 kDa ribosomal S6 kinase) family comprises a group of highly related serine/threonine ... more The RSK (90 kDa ribosomal S6 kinase) family comprises a group of highly related serine/threonine kinases that regulate diverse cellular processes, including cell growth, proliferation, survival and motility. This family includes four vertebrate isoforms (RSK1, RSK2, RSK3 and RSK4), and single family member orthologues are also present in Drosophila and Caenorhabditis elegans. The RSK isoforms are downstream effectors of the Ras/ERK (extracellular-signal-regulated kinase) signalling pathway. Significant advances in the field of RSK signalling have occurred in the past few years, including several new functions ascribed to the RSK isoforms, the discovery of novel protein substrates and the implication of different RSK isoforms in cancer. Collectively, these new findings increase the diversity of biological functions regulated by RSK, and highlight potential new directions of research. In the present paper, we review the structure, expression and activation mechanisms of the RSK isoforms, and discuss their physiological roles on the basis of established substrates and recent discoveries. initiation factor; 4E-BP1, eIF4E-binding protein 1; Emi, early mitotic inhibitor; ERα, oestrogen receptor α; ERK, extracellular-signal-regulated kinase; Erp1, Emi1-related protein; EST, expressed sequence tag; ETS, E twenty-six; Elk1, ETS-like kinase 1; FGFR3, fibroblast growth factor receptor 3; FMK, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone; GLUT4, glucose transporter 4; GSK3, glycogen synthase kinase-3; IκB, inhibitor of nuclear factor κB; IEG, immediate-early gene; IFN, interferon; KIM, kinase interaction motif; LKB1, liver kinase B1; Mad, mitotic arrest-deficient protein; MAP, microtuble-associated protein; MAPK, mitogen-activated protein kinase; MDCK cell, Madin-Darby canine kidney cell; MEK, MAPK/ERK kinase; MK, MAPK-activated protein kinase; MSK, mitogen-and stress-activated kinase; mTOR, mammalian target of rapamycin; Myt1, myelin transcription factor 1; NF-κB, nuclear factor κB; NOS, nitric oxide synthase; nNOS, neuronal NOS; NTKD, N-terminal kinase domain; p27 kip1 , cyclin-dependent kinase inhibitor 1B; PAK1, p21-activated kinase-1; PDK1, 3 -phosphoinositide-dependent protein kinase 1; PEA-15, phosphoprotein enriched in astrocytes, 15 kDa; PIF, PDK1-interacting fragment; PKA, protein kinase A; RanBP3, Ran-binding protein 3; RNAi, RNA interference; rpS6, ribosomal protein S6; RSK, 90 kDa ribosomal S6 kinase; S6K, S6 kinase; SGK, serum-and glucocorticoid-induced protein kinase; SOS, son of sevenless; SRF, serum-response factor; TSC2, tuberous sclerosis complex 2; YB-1, Y-box binding protein-1.

Research paper thumbnail of Cell Growth Regulation by PI3-kinase, Ras and mTOR Signal Integration

Research paper thumbnail of The expanding role of mTOR in cancer cell growth and proliferation

Mutagenesis, 2015

The mechanistic/mammalian target of rapamycin (mTOR) is a conserved protein kinase that controls ... more The mechanistic/mammalian target of rapamycin (mTOR) is a conserved protein kinase that controls several anabolic processes required for cell growth and proliferation. As such, mTOR has been implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes and neurodegeneration. As part of the mTOR complex 1 (mTORC1), mTOR regulates cell growth by promoting the biosynthesis of proteins, lipids and nucleic acids. Several mTORC1 substrates have been shown to regulate protein synthesis, including the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs) and the ribosomal S6 kinases (S6Ks) 1 and 2. In this work, we focus on the signalling pathways that lie both upstream and downstream of mTORC1, as well as their relevance to human pathologies. We further discuss pharmacological approaches that target mTOR and their applications for the treatment of cancer.

Research paper thumbnail of Translational control by oncogenic signaling pathways

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 2014

Research paper thumbnail of Rapamycin Resistance: mTORC1 Substrates Hold Some of the Answers

Current Biology, 2013

2010). Where's the glass? Biomarkers, molecular clocks, and microRNAs suggest a 200-Myr missing P... more 2010). Where's the glass? Biomarkers, molecular clocks, and microRNAs suggest a 200-Myr missing Precambrian fossil record of siliceous sponge spicules. Geobiology 8, 24-36. 9. Antcliffe, J., Callow, R., and Brasier, M. (2013).

Research paper thumbnail of Insulin Activates RSK (p90 Ribosomal S6 Kinase) to Trigger a New Negative Feedback Loop That Regulates Insulin Signaling for Glucose Metabolism

Journal of Biological Chemistry, 2013

Background: RSK is a downstream effector of the Ras/ERK pathway and shares high homology with S6K... more Background: RSK is a downstream effector of the Ras/ERK pathway and shares high homology with S6K. Results: RSK1 inhibition improved insulin signaling and insulin action on glucose metabolism in myotubes and hepatocytes by preventing IRS-1 Ser-1101 phosphorylation. Conclusion: RSK1 promotes insulin resistance by phosphorylating IRS-1 Ser-1101. Significance: RSK1 might be a new mediator of insulin resistance in hyperinsulinemia or diabetic states. The abbreviations used are: IRG, insulin receptor substrate; 2-DG, 2-deoxyglucose; AA, amino acid; RSK, p90 ribosomal S6 kinase; mTOR, mammalian target of rapamycin; S6K1, p70 S6 kinase; CTKD, C-terminal kinase domains; NTKD, N-terminal kinase domains.

Research paper thumbnail of Phosphoproteomic analysis identifies the tumor suppressor PDCD4 as a RSK substrate negatively regulated by 14-3-3

Proceedings of the National Academy of Sciences of the United States of America, Jan 22, 2014

The Ras/MAPK signaling cascade regulates various biological functions, including cell growth and ... more The Ras/MAPK signaling cascade regulates various biological functions, including cell growth and proliferation. As such, this pathway is frequently deregulated in several types of cancer, including most cases of melanoma. RSK (p90 ribosomal S6 kinase) is a MAPK-activated protein kinase required for melanoma growth and proliferation, but relatively little is known about its exact function and the nature of its substrates. Herein, we used a quantitative phosphoproteomics approach to define the signaling networks regulated by RSK in melanoma. To more accurately predict direct phosphorylation substrates, we defined the RSK consensus phosphorylation motif and found significant overlap with the binding consensus of 14-3-3 proteins. We thus characterized the phospho-dependent 14-3-3 interactome in melanoma cells and found that a large proportion of 14-3-3 binding proteins are also potential RSK substrates. Our results show that RSK phosphorylates the tumor suppressor PDCD4 (programmed cell...

Research paper thumbnail of Casein Kinase 1  Promotes Cell Proliferation by Regulating mRNA Translation

Cancer Research, 2014

Deregulation of translation initiation factors contributes to many pathogenic conditions, includi... more Deregulation of translation initiation factors contributes to many pathogenic conditions, including cancer. Here, we report the definition of a novel regulatory pathway for translational initiation with possible therapeutic import in cancer. Specifically, we found that casein kinase 1e (CK1e) is highly expressed in breast tumors and plays a critical role in cancer cell proliferation by controlling mRNA translation. Eukaryotic translation initiation factor eIF4E, an essential component of the translation initiation complex eIF4F, is downregulated by binding the negative-acting factor 4E-BP1. We found that genetic or pharmacologic inhibition of CK1e attenuated 4E-BP1 phosphorylation, thereby increasing 4E-BP1 binding to eIF4E and inhibiting mRNA translation. Mechanistic investigations showed that CK1e interacted with and phosphorylated 4E-BP1 at two novel sites T41 and T50, which were essential for 4E-BP1 inactivation along with increased mRNA translation and cell proliferation. In summary, our work identified CK1e as a pivotal regulator of mRNA translation and cell proliferation that acts by inhibiting 4E-BP1 function. As CK1e is highly expressed in breast tumors, these findings offer an initial rationale to explore CK1e blockade as a therapeutic strategy to treat cancers driven by deregulated mRNA translation. Cancer Res; 74(1); 201-11. Ó2013 AACR.