Activation of Extracellular Signal-Regulated Kinase but Not of p38 Mitogen-Activated Protein Kinase Pathways in Lymphocytes Requires Allosteric Activation of SOS

Jun, Jesse E.; Yang, Ming; Chen, Hang; Chakraborty, Arup K.; Roose, Jeroen P.

doi:10.1128/mcb.01593-12

Cited by 20 publications

(48 citation statements)

References 79 publications

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“…To our knowledge ours is the first report showing that SOS1 is an activator of NFκB. The F929A mutation of SOS1 abrogates its ability to catalyze guanine nucleotide exchange (35,36) but not its ability to activate NFκB. We demonstrate that F929A mutant SOS1 increases erlotinib resistance and NFκB activation with an efficiency similar to that of wild-type SOS1.…”

Section: Discussionmentioning

confidence: 57%

“…Therefore, increased expression of SOS1 mediates erlotinib resistance. To determine whether the catalytic activity of SOS1 is required, the catalytically dead F929A mutant (35,36) was stably expressed in PC9 cells. The resistance of these cells was similar to cells in which the wild-type SOS1 was overexpressed (Fig.…”

Section: Egfr Mediates Nfκb Activation In Several Cancer Cell Linesmentioning

confidence: 99%

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EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells

Dermawan

Stark

2014

Proc. Natl. Acad. Sci. U.S.A.

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Activation of nuclear factor κB (NFκB) is a central event in the responses of normal cells to inflammatory signals, and the abnormal constitutive activation of NFκB is important for the survival of most cancer cells. In nonmalignant human cells, EGF stimulates robust activation of NFκB. The kinase activity of the EGF receptor (EGFR) is required, because the potent and specific inhibitor erlotinib blocks the response. Down-regulating EGFR expression or inhibiting EGFR with erlotinib impairs constitutive NFκB activation in several different types of cancer cells and, conversely, increased activation of NFκB leads to erlotinib resistance in these cells. We conclude that EGF is an important mediator of NFκB activation in cancer cells. To explore the mechanism, we selected an erlotinibresistant cell line in which the guanine nucleotide exchange factor Son of Sevenless 1 (SOS1), well known to be important for EGFdependent signaling to MAP kinases, is overexpressed. Increased expression of SOS1 increases NFκB activation in several different types of cancer cells, and ablation of SOS1 inhibits EGF-induced NFκB activation in these cells, indicating that SOS1 is a functional component of the pathway connecting EGFR to NFκB activation. Importantly, the guanine nucleotide exchange activity of SOS1 is not required for NFκB activation.

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Section: Discussionmentioning

confidence: 57%

Section: Egfr Mediates Nfκb Activation In Several Cancer Cell Linesmentioning

confidence: 99%

EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells

Dermawan

Stark

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…A recent study also reports that SOS1/2 maybe inhibitory for TCR-induced ERK activation in human peripheral T cells (140), although this finding is inconsistent with several other studies showing a positive contribution of SOS in antigen receptor-stimulated ERK activation, both in lymphocyte cell lines and primary mouse and human lymphocytes (20, 65–67, 92). Reduction of SOS expression leads to moderate but consistent ERK activation impairment in human peripheral T cells, mouse DP thymocytes, and DT40 B cell line (20, 66, 67, 92, 139). Furthermore, the ERK activation defect in SOS1 − 2 − DT40 cells is most noticeable at low and physiological levels of antigen receptor stimulation, indicating that ranges of stimuli across multiple time points are required to conclusively analyze ERK activation defects (66, 92, 139).…”

Section: Biochemical Synergy Between Sos1 and Rasgrp1mentioning

confidence: 67%

“…Ectopic expression studies provided in vivo evidence of allosteric regulation of SOS1 in COS-1 cells (89, 91) or Jurkat cells (65, 66). Recently, allosteric mutant-SOS1 reconstitution into SOS-deficient mESC (87) and DT40 B cells (92) provided more definitive proof of allosteric SOS1 activation regulating the output through the Ras-ERK pathway. In addition to enhancing catalytic activity of SOS, allosteric Ras·GTP binding could potentially affect SOS residence time at the PM by providing an additional membrane anchor for SOS1 other than Grb2 binding.…”

Section: Allosteric Activation Of Sos; a Positive Feedback Loopmentioning

confidence: 99%

“…However, genetic studies in cell lines and mice indicate that RasGRP plays a more dominant role in antigen receptor-stimulated Ras-ERK activation (18, 61, 66, 67, 92, 139). A recent study also reports that SOS1/2 maybe inhibitory for TCR-induced ERK activation in human peripheral T cells (140), although this finding is inconsistent with several other studies showing a positive contribution of SOS in antigen receptor-stimulated ERK activation, both in lymphocyte cell lines and primary mouse and human lymphocytes (20, 65–67, 92). Reduction of SOS expression leads to moderate but consistent ERK activation impairment in human peripheral T cells, mouse DP thymocytes, and DT40 B cell line (20, 66, 67, 92, 139).…”

Section: Biochemical Synergy Between Sos1 and Rasgrp1mentioning

confidence: 99%

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Regulation of Ras Exchange Factors and Cellular Localization of Ras Activation by Lipid Messengers in T Cells

Jun¹,

Rubio²,

Roose³

2013

Front. Immunol.

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The Ras-MAPK signaling pathway is highly conserved throughout evolution and is activated downstream of a wide range of receptor stimuli. Ras guanine nucleotide exchange factors (RasGEFs) catalyze GTP loading of Ras and play a pivotal role in regulating receptor-ligand induced Ras activity. In T cells, three families of functionally important RasGEFs are expressed: RasGRF, RasGRP, and Son of Sevenless (SOS)-family GEFs. Early on it was recognized that Ras activation is critical for T cell development and that the RasGEFs play an important role herein. More recent work has revealed that nuances in Ras activation appear to significantly impact T cell development and selection. These nuances include distinct biochemical patterns of analog versus digital Ras activation, differences in cellular localization of Ras activation, and intricate interplays between the RasGEFs during distinct T cell developmental stages as revealed by various new mouse models. In many instances, the exact nature of these nuances in Ras activation or how these may result from fine-tuning of the RasGEFs is not understood. One large group of biomolecules critically involved in the control of RasGEFs functions are lipid second messengers. Multiple, yet distinct lipid products are generated following T cell receptor (TCR) stimulation and bind to different domains in the RasGRP and SOS RasGEFs to facilitate the activation of the membrane-anchored Ras GTPases. In this review we highlight how different lipid-based elements are generated by various enzymes downstream of the TCR and other receptors and how these dynamic and interrelated lipid products may fine-tune Ras activation by RasGEFs in developing T cells.

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Gene expression profile analysis of SUDHL6 cells with siRNA‐mediated BCL11A downregulation

Gao

Ding

et al. 2014

Cell Biology International

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Our previous study has shown that downregulation of B-cell chronic lymphocytic leukemia (CLL)/lymphoma11A (BCL11A) gene by small interfering RNA (siRNA) resulted in the growth inhibition and apoptosis of B cell lymphoma cell line SUDHL6. To gain further insight into the molecular mechanisms of this process and identify the differentially expressed genes in SUDHL6 cells after BCL11A downregulation, the global gene expression profile was identified and analyzed using the Affymetrix HG-U133 Plus 2.0 array. Twenty-one differentially expressed genes were validated and analyzed from the BCL11A siRNA-treated SUDHL6 cells. There was a significant dysregulation in the global gene expression of the BCL11A-suppressed SUDHL6 cells. There were 1903 genes differentially expressed with >2-fold changes between the BCL11A siRNA- and negative control-transfected cells. Of these, there were 916 upregulated genes and 987 downregulated genes. The differential genes are involved in various molecular functions and signaling pathways. QRT-PCR validation of the selected differentially expressed genes demonstrated there was a good correlation with the microarray analysis. There was a significant deregulation of expression in the apoptosis-related genes such as BCL-2, BCL2L11 and involved in TGFβ, MAPK, WNT signaling pathways after BCL11A was downregulated in SUDHL6 cells. Our results show that the suppression of BCL11A by RNA interference altered gene expression profile of SUDHL6 cells. The apoptosis-related genes BCL-2, BCL2L11 and the gene alterations in TGFβ, MAPK, WNT signaling pathways might be important in BCL11A siRNA-induced apoptosis of SUDHL6 cells, suggesting BCL11A is involved in gene networks associated with apoptosis.

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Activation of Extracellular Signal-Regulated Kinase but Not of p38 Mitogen-Activated Protein Kinase Pathways in Lymphocytes Requires Allosteric Activation of SOS

Cited by 20 publications

References 79 publications

EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells

EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells

Regulation of Ras Exchange Factors and Cellular Localization of Ras Activation by Lipid Messengers in T Cells

Gene expression profile analysis of SUDHL6 cells with siRNA‐mediated BCL11A downregulation

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