A 50-kDa ERK-like protein is up-regulated by a dual altered peptide ligand that suppresses myasthenia gravis-associated responses

Ben-David, Hava; Aruna, Badiga Venkata; Seger, Rony; Sela, Michael; Mozes, Edna

doi:10.1073/pnas.0608896103

Cited by 9 publications

(4 citation statements)

References 36 publications

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“…Blocking of PDGFRα+β leads to changes in ERK and, further downstream, the increase of hexokinase-2 expression resulting in higher metabolic glucose demand as measured with [ 18 F]FDG. Changes in pERK levels and altered ERK isofroms have been documented previously with our work on changes in PDGFRA signalling and blockade (Ekpe et al 2016), as well as by Ben-David et al (2006) and Sabbatino et al (2014). The relationship between ERK signalling and [18F]FDG uptake has also been well documented in clinical analysis of MEK inhibitors in different metastatic solid tumours, whereby decreased ERK activity follows a reduction in [ 18 F]FDG uptake (Kraeber-Bodéré et al 2012).…”

Section: Discussionsupporting

confidence: 75%

Tyrosine kinase inhibitor therapy and metabolic remodelling in papillary thyroid cancer

Wagner

Wuest

Lopez-Campistrous

et al. 2020

Endocrine-Related Cancer

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The present study used [18F]FDG-PET to study glucose metabolism and tumor responses for thyroid cancer xenografts expressing the glycolytic pathway modulators platelet-derived growth factor receptor (PDGFR) and BRAFV600E. PET data were correlated with immunohistochemistry staining and kinetic analysis for facilitative glucose transporter 1 (GLUT1) and hexokinase-II (HK2). Vemurafenib decreased [18F]FDG uptake in BCPAP cells in vitro; however, it was increased by ~70% with imatinib application to BCPAP cells. This metabolic response to tyrosine kinase inhibition required BRAFV600E as it was not observed in cell lines lacking mutated BRAF (TPC1). In xenografts, imatinib therapy in BCPAP thyroid tumour-bearing mice significantly increased [18F]FDG uptake and retention (>30%) in BCPAP tumours with PDGFRβ or both (α+β) isoforms. Kinetic analysis revealed that the increased glucose uptake is a consequence of increased phosphorylation and intracellular trapping of [18F]FDG confirmed by an increase in HK2 protein expression and activity, but not GLUT1 activity. BRAF inhibition alone, or combined PDGFR and BRAF inhibition, reduced (~60%) [18F]FDG uptake in both types of BCPAP (β or α+β) tumours. Combination therapy with imatinib and vemurafenib led to a near abolition of the tumors (~90% reduction). Still, single treatment for BCPAP with PDGFRα expression was much less effective. In summary, imatinib led to a paradoxical increase of [18F]FDG uptake in xenografts that was reversed through BRAFV600E inhibition. Our data show that metabolic reprogramming in thyroid cancer occurs as a consequence of BRAF-mediated upregulation of HK2 expression that may permit tumour growth with isolated blockade of upstream tyrosine kinase receptors.

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Section: Discussionsupporting

confidence: 75%

Tyrosine kinase inhibitor therapy and metabolic remodelling in papillary thyroid cancer

Wagner

Wuest

Lopez-Campistrous

et al. 2020

Endocrine-Related Cancer

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“…A functional impairment of thymic Treg cells was found in the thymus of MG patients and may thus be involved in the onset of the autoimmune process (14). CD4 ϩ CD25 ϩ cells were found to be functionally involved in the suppressive action of various effective therapies demonstrated by us and by others in the mouse and rat experimental models for MG (15)(16)(17)(18)(19)(20), suggesting that modulation of the CD4 ϩ CD25 ϩ cell compartment could play a key role in the treatment of myasthenia. The knowledge on Treg cell induction and activation opens the possibility of an attractive approach for immunotherapy of autoimmune diseases.…”

Section: Most Endogenous Cd4mentioning

confidence: 99%

Ex Vivo Generated Regulatory T Cells Modulate Experimental Autoimmune Myasthenia Gravis

Aricha

Feferman

Fuchs

et al. 2008

The Journal of Immunology

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Naturally occurring CD4+CD25+ regulatory T (Treg) cells are key players in immune tolerance and have therefore been suggested as potential therapeutic tools for autoimmune diseases. In myasthenia gravis (MG), reduced numbers or functionally impaired Treg cells have been reported. We have observed that PBL from myasthenic rats contain decreased numbers of CD4+CD25highFoxp3+ cells as compared with PBL from healthy controls, and we have tested whether Treg cells from healthy donors can suppress experimental autoimmune MG in rats. Because the number of naturally occurring Treg cells is low, we used an approach for a large-scale ex vivo generation of functional Treg cells from CD4+ splenocytes of healthy donor rats. Treg cells were generated ex vivo from CD4+ cells by stimulation with anti-CD3 and anti-CD28 Abs in the presence of TGF-β and IL-2. The obtained cells expressed high levels of CD25, CTLA-4, and Foxp3, and they were capable of suppressing in vitro proliferation of T cells from myasthenic rats in response to acetylcholine receptor, the major autoantigen in myasthenia. Administration of ex vivo-generated Treg cells to myasthenic rats inhibited the progression of experimental autoimmune MG and led to down-regulation of humoral acetylcholine receptor-specific responses, and to decreased IL-18 and IL-10 expression. The number of CD4+CD25+ cells in the spleen of treated rats remained unchanged, but the subpopulation of CD4+CD25+ cells expressing Foxp3 was significantly elevated. Our findings imply that Treg cells play a critical role in the control of myasthenia and could thus be considered as potential agents for the treatment of MG patients.

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“…Different alternatively spliced forms were also reported for ERK5 (Yan et al 2001), MEK5 (English et al 1995), JNK (Gupta et al 1996), MKK7 (Tournier et al 1999), and others. In addition, besides ERK1c, two alternatively spliced forms-ERK1b (Yung et al 2000) and ERK2b (Gonzalez et al 1992)-have been reported for ERKs, and other forms may exist as well (Ben-David et al 2006). Thus, alternatively spliced isoforms of components of MAPK cascades add to the complexity of the signaling network, which allows the regulation of the wide range of processes governed by these cascades.…”

Section: Mek1b-erk1c Is An Erk Cascade Subroutementioning

confidence: 99%

Specific phosphorylation and activation of ERK1c by MEK1b: a unique route in the ERK cascade

Shaul¹,

Gibor²,

Plotnikov³

et al. 2009

Genes Dev.

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Extracellular signal-regulated kinases (ERKs) are key signaling molecules that regulate a large number of cellular processes, including mitosis. We showed previously that ERK1c, an alternatively spliced form of ERK1, facilitates mitotic Golgi fragmentation without the involvement of ERK1 and ERK2. Here we demonstrate that activation of ERK1c is mainly mediated by mitogen-activated protein kinase (MAPK)/ERK kinase 1b (MEK1b), which is an alternatively spliced form of MEK1 that was previously considered an inactive kinase. MEK1b phosphorylation and activity are preferentially stimulated by nocodazole, to induce its specific activity toward ERK1c. MEK1/2, on the other hand, preferentially target ERK1/2 in response to growth factors, such as EGF. As previously demonstrated for ERK1c, also MEK1b expression and activity are elevated during mitosis, and thereby enhance Golgi fragmentation and mitotic rate. MEK1 activity is also increased during mitosis, but this isoform facilitates mitotic progression without affecting the Golgi architecture. These results illustrate that the ERK cascade is divided into two routes: the classic MEK1/2-ERK1/2 and the splice-variant MEK1b-ERK1c, each of which regulates distinct cellular processes and thus extends the cascade specificity.[Keywords: MEK; ERK; signaling cascades; Golgi fragmentation; cell cycle] Supplemental material is available at http://www.genesdev.org.

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A 50-kDa ERK-like protein is up-regulated by a dual altered peptide ligand that suppresses myasthenia gravis-associated responses

Cited by 9 publications

References 36 publications

Tyrosine kinase inhibitor therapy and metabolic remodelling in papillary thyroid cancer

Tyrosine kinase inhibitor therapy and metabolic remodelling in papillary thyroid cancer

Ex Vivo Generated Regulatory T Cells Modulate Experimental Autoimmune Myasthenia Gravis

Specific phosphorylation and activation of ERK1c by MEK1b: a unique route in the ERK cascade

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