Growth factor pleiotropy is controlled by a receptor Tyr/Ser motif that acts as a binary switch

Guthridge, Mark A.; Powell, Jason A.; Barry, Emma F.; Stomski, Frank C.; McClure, Barbara J.; Ramshaw, Hayley S.; Felquer, Fernando; Dottore, Mara; Thomas, Daniel; To, Bik; Begley, C. Glenn; Lopez, Angel F.

doi:10.1038/sj.emboj.7600948

Cited by 74 publications

(102 citation statements)

References 51 publications

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“…Tyr 179 of 14-3-3 Is Important for the Assembly of a PI 3-Kinase Signaling Complex in Response to Cytokine-Our findings, as well as those of others, have shown that both 14-3-3 and Shc are important for the regulation of PI 3-kinase signaling in response to GM-CSF (10,12,18). We therefore examined the possibility that the binding of Shc to Tyr 179 of 14-3-3 in response to GM-CSF stimulation may be necessary for the assembly of an active PI 3-kinase signaling complex.…”

Section: Gst-sh2mentioning

confidence: 65%

“…We have previously shown that there are two distinct cell survival pathways emanating from the ␤c subunit of the GM-CSF receptor: one that promotes ␤cSer 585 phosphorylation and 14-3-3 binding and the other that promotes ␤cTyr 577 phosphorylation and Shc binding (9,10). This raised the possibility that 14-3-3 and Shc may form part of a ␤c receptor-proximal signaling scaffold involved in regulating cytokine function.…”

Section: Cytokine-mediated Interaction Of Endogenous 14-3-3 and Shc-mentioning

confidence: 99%

“…The myelomonocytic UT7 factordependent cell line was cultured in RPMI and 10% FCS supplemented with 2 ng/ml GM-CSF. Mononuclear cells were purified from normal donors as previously described (10). CTL-EN and UT7 cells were electroporated with constructs for the expression of 14-3-3-Myc (20 g), Akt-HA (5 g), and/or ERK-HA (5 g).…”

Section: Methodsmentioning

confidence: 99%

“…Our previous results showed that the ␤c subunit of the GM-CSF receptor is able to promote PI 3-kinase activation via two pathways; one pathway is regulated via Tyr 577 of ␤c, which binds Shc, and the other pathway is regulated via Ser 585 of ␤c, which binds 14-3-3 (9, 10, 12). Importantly, although no reduction in cell survival or proliferation in response to high concentrations of cytokine (Ͼ10 pM) was observed in either the Y577F or the S585G single mutants, these biological responses were defective in the Y577F/S585G double mutant (9,10,12). Thus, our results indicated that Tyr 577 could compensate for the loss of Ser 585 , whereas Ser 585 could compensate for the loss of Tyr 577 .…”

Section: Gst-sh2mentioning

confidence: 99%

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14-3-3:Shc Scaffolds Integrate Phosphoserine and Phosphotyrosine Signaling to Regulate Phosphatidylinositol 3-Kinase Activation and Cell Survival

Barry

Felquer

Powell

et al. 2009

Journal of Biological Chemistry

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Integrated cascades of protein tyrosine and serine/threonine phosphorylation play essential roles in transducing signals in response to growth factors and cytokines. How adaptor or scaffold proteins assemble signaling complexes through both phosphotyrosine and phosphoserine/threonine residues to regulate specific signaling pathways and biological responses is unclear. We show in multiple cell types that endogenous 14-3-3 is phosphorylated on Tyr 179 in response to granulocyte macrophage colony-stimulating factor. Importantly, 14-3-3 can function as an intermolecular bridge that couples to phosphoserine residues and also directly binds the SH2 domain of Shc via Tyr 179 . The assembly of these 14-3-3:Shc scaffolds is specifically required for the recruitment of a phosphatidylinositol 3-kinase signaling complex and the regulation of CTL-EN cell survival in response to cytokine. The biological significance of these findings was further demonstrated using primary bone marrow-derived mast cells from 14-3-3 ؊/؊ mice. We show that cytokine was able to promote Akt phosphorylation and viability of primary mast cells derived from 14-3-3 ؊/؊ mice when reconstituted with wild type 14-3-3, but the Akt phosphorylation and survival response was reduced in cells reconstituted with the Y179F mutant. Together, these results show that 14-3-3:Shc scaffolds can act as multivalent signaling nodes for the integration of both phosphoserine/threonine and phosphotyrosine pathways to regulate specific cellular responses.

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Section: Gst-sh2mentioning

confidence: 65%

Section: Cytokine-mediated Interaction Of Endogenous 14-3-3 and Shc-mentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Gst-sh2mentioning

confidence: 99%

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14-3-3:Shc Scaffolds Integrate Phosphoserine and Phosphotyrosine Signaling to Regulate Phosphatidylinositol 3-Kinase Activation and Cell Survival

Barry

Felquer

Powell

et al. 2009

Journal of Biological Chemistry

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“…Y577, Y612 and Y695 in JAK-2 were sufficient to signal proliferation. Observations in human GM-CSF responsive cell lines identified that phosphorylation of a conserved serine residue, S585, was critical for suppressing apoptosis, particularly at limiting concentrations of cytokine [42]. At low doses cells survived but did not proliferate and ßc was phosphorylated at S585 but not at Y577.…”

Section: Signalling Kinasesmentioning

confidence: 99%

Critical Evaluation of Antiepileptic Drugs in Epileptic Pregnant Women - Hungarian Experiences

Ekert¹,

Jabbour²

2011

Open Cell Signal J

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It has long been known that many cell types are dependent on specific cytokines that signal proliferation, regulate differentiation and suppress apoptosis. A detailed picture of the structure of several cytokine receptors has added to our understanding of the molecular mechanism of receptor activation. An explosion of knowledge of apoptosis pathways and the ways in which the Bcl-2 family of proteins function has deepened the understanding of the effector arm of the programmed cell death pathway. The challenge is to uncover the molecular links between these two pathways. In this article, we will try to examine what is known of the intersections between cytokine signalling pathways and apoptosis pathways, with particular reference to receptor signalling by the haematopoietic cytokines Interleukin-3 (IL-3) and Granulocyte-Macrophage-Colony Stimulating Factor (GM-CSF).

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Interleukin 3, Interleukin 5, and Granulocyte–Macrophage Colony‐Stimulating Factor

Llop‐Guevara¹,

Marcinko²,

Fattouh³

et al. 2011

Inflammation and Allergy Drug Design

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Computational analysis has become an indispensable bioinformatics approaches for the characterization of proteins regarding the physicochemical properties, prediction of signal peptides and 3D structure. Additionally, computational studies of protein-ligand interactions provide a rational basis for the speedy identification of novel leads for drug. To date no any computational analysis evaluating such parameters for GM-CSF-Rα, IL-3-Rα and IL-5-Rα. Hence, the present work aimed at identifying the theoretical basis of the physicochemical, structural and functional proprieties for these proteins using online computational tools. In the present study, different bioinformatics tools were used to characterize the properties and structure of the GM-CSF-Rα, IL3Rα, and IL5Rα proteins. Firstly, the Physico-chemical characterization was computed by ExPasy's (ProtParam). Then Fingerprinting analysis was done with ScanProsite. Followed by the functional characterization of the transmembrane regions and phosphorylation sites using SOSUI server and NetPhos server respectively. Afterwards, secondary structure prediction and the protein-ligand binding site residues were predicted by PDBSUM, and the detected ligands and their interactions were visualized by LIGPLOT and Protein ligand interaction profiler (PILP) softwares. The residues in GM-CSF-Rα, IL-3Rα and IL-5Rα proteins that may undergo ubiquitination were detected by using the UbPred and BDM-PUB programs, the predicted peptides for sumoylation in GM-CSF-Rα, IL-3Rα and IL-5Rα proteins were detected by GPS-SUMO online service. Finally, the 3D structure of proteins was built by Chimera 1.8 program. In addition, the models were surveyed using ERRAT server; as a confirmation for the quality of the models. Our results revealed that GM-CSF-Rα is stable whereas the IL3Rα and IL5Rα are classified as unstable proteins. All proteins are membrane proteins, acidic and hydrophilic in nature, with serine being the most phosphorylated amino acid. Interestingly, fibronectin type-III (FN3) domain was detected among these proteins. Also, we detected the sequences belonging to the following families: HEMATOPO_REC_S_F2, ASN_GLYCOSYLATION, CK2_PHOSPHO_SITE, PKC_PHOSPHO_SITE, MYRISTYL, CAMP_PHOSPHO_SITE, and TYR_PHOSPHO. Moreover, we detected 9 kinases in GM-CSF-Rα, while 13 kinases in IL-3-Rα and 15 kinases in IL-5-Rα. In GM-CSF-Rα 3 binding sites were detected with two ligands (GOL and NAG), and 5 binding sites in IL-3-Rα and IL-5-Rα with 3ligands (NAG, FUL and BMA) and one ligand (BGC) respectively. Secondary structure prediction showed that Beta sheet dominated all the other conformations. Modeling the 3 D structure of proteins resulted in a quality of less than 90%. computational analysis of GM-CSF-Rα, IL-3-Rα and IL-5-Rα will give a deep insight and provide opportunities for understanding the function of these proteins, and developing novel therapeutics for treating certain leukemia and inflammatory diseases.

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Growth factor pleiotropy is controlled by a receptor Tyr/Ser motif that acts as a binary switch

Cited by 74 publications

References 51 publications

14-3-3:Shc Scaffolds Integrate Phosphoserine and Phosphotyrosine Signaling to Regulate Phosphatidylinositol 3-Kinase Activation and Cell Survival

14-3-3:Shc Scaffolds Integrate Phosphoserine and Phosphotyrosine Signaling to Regulate Phosphatidylinositol 3-Kinase Activation and Cell Survival

Critical Evaluation of Antiepileptic Drugs in Epileptic Pregnant Women - Hungarian Experiences

Interleukin 3, Interleukin 5, and Granulocyte–Macrophage Colony‐Stimulating Factor

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