Proteasome-dependent regulation of Syk tyrosine kinase levels in human basophils

Youssef, Lama A.; Wilson, Bridget S.; Oliver, Janet M.

doi:10.1067/mai.2002.127562

Cited by 24 publications

(37 citation statements)

References 29 publications

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“…Evidence from several laboratories has demonstrated that Syk is highly susceptible to the Ub proteasome-mediated proteolysis in both resting and activated hemopoietic cell types (16,24,25,27). In the present investigation, we have found that proteasome inhibitors restored Syk expression in CIN85-overexpressing cells (Fig.…”

Section: Discussionsupporting

confidence: 71%

“…Our results support previous evidence for proteasomedependent pathways in the regulation of Syk tyrosine kinase expression (16,(23)(24)(25) and provide a mechanism for this regulation involving the action of CIN85 and Cbl proteins.…”

supporting

confidence: 81%

“…The explanation very likely lies in additional effect(s) of proteasome inhibitors occurring upstream and/or downstream to Syk. Relevant to this, Youssef et al (24) have reported a dramatic impairment of receptor phosphorylation on human basophils treated with proteasome inhibitor I.…”

Section: Discussionmentioning

confidence: 99%

“…Work by many research groups including our own, implicates proteasome-dependent mechanisms in the regulation of Syk tyrosine kinase expression levels in both resting and activated human basophils and RBL-2H3 cells (16,24,25). To investigate whether CIN85 overexpression could affect the steady state protein level of Syk by promoting proteasome degradation, cells were treated with cell-permeable protease inhibitors or with a corresponding volume of the vehicle DMSO as control and analyzed after 8 h for the expression of Syk by Western blotting on whole cell lysates.…”

Section: Proteasome Inhibitors Restore Syk Protein Levels In Cin85-ovmentioning

confidence: 99%

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The Adaptor Molecule CIN85 Regulates Syk Tyrosine Kinase Level by Activating the Ubiquitin-Proteasome Degradation Pathway

Peruzzi

Molfetta

Gasparrini

et al. 2007

The Journal of Immunology

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Triggering of mast cells and basophils by IgE and Ag initiates a cascade of biochemical events that lead to cell degranulation and the release of allergic mediators. Receptor aggregation also induces a series of biochemical events capable of limiting FcεRI-triggered signals and functional responses. Relevant to this, we have recently demonstrated that Cbl-interacting 85-kDa protein (CIN85), a multiadaptor protein mainly involved in the process of endocytosis and vesicle trafficking, regulates the Ag-dependent endocytosis of the IgE receptor, with consequent impairment of FcεRI-mediated cell degranulation. The purpose of this study was to further investigate whether CIN85 could alter the FcεRI-mediated signaling by affecting the activity and/or expression of molecules directly implicated in signal propagation. We found that CIN85 overexpression inhibits the FcεRI-induced tyrosine phosphorylation of phospholipase Cγ, thus altering calcium mobilization. This functional defect is associated with a substantial decrease of Syk protein levels, which are restored by the use of selective proteasome inhibitors, and it is mainly due to the action of the ubiquitin ligase c-Cbl. Furthermore, coimmunoprecipitation experiments demonstrate that CIN85 overexpression limits the ability of Cbl to bind suppressor of TCR signaling 1 (Sts1), a negative regulator of Cbl functions, while CIN85 knockdown favors the formation of Cbl/Sts1 complexes. Altogether, our findings support a new role for CIN85 in regulating Syk protein levels in RBL-2H3 cells through the activation of the ubiquitin-proteasome pathway and provide a mechanism for this regulation involving c-Cbl ligase activity.

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Section: Discussionsupporting

confidence: 71%

supporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Proteasome Inhibitors Restore Syk Protein Levels In Cin85-ovmentioning

confidence: 99%

See 2 more Smart Citations

The Adaptor Molecule CIN85 Regulates Syk Tyrosine Kinase Level by Activating the Ubiquitin-Proteasome Degradation Pathway

Peruzzi

Molfetta

Gasparrini

et al. 2007

The Journal of Immunology

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“…Cross-linking IgE-bound FcRI on the basophil surface with anti-IgE Ab or polyvalent allergen elicits calcium-dependent degranulation, as well as cytoskeletal reorganization, membrane ruffling, the up-regulation of ␤ 1 integrin adhesive activity, and the de novo synthesis of leukotrienes and cytokines (1). Basophils from a minority of subjects fail to secrete histamine, increase integrin-mediated adhesion, or produce IL-4 in response to FcRI cross-linking (2)(3)(4)(5)(6)(7)(8). The unresponsiveness of "nonreleaser" basophils has been linked to the increased proteasomal degradation of Syk, an essential tyrosine kinase in the FcRI-signaling cascade (5,9).…”

mentioning

confidence: 99%

Histamine Release from the Basophils of Control and Asthmatic Subjects and a Comparison of Gene Expression between “Releaser” and “Nonreleaser” Basophils

Youssef

Schuyler²,

Gilmartin

et al. 2007

The Journal of Immunology

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Most human blood basophils respond to FcεRI cross-linking by releasing histamine and other inflammatory mediators. Basophils that do not degranulate after anti-IgE challenge, known as “nonreleaser” basophils, characteristically have no or barely detectable levels of the Syk tyrosine kinase. The true incidence of the nonreleaser phenotype, its relationship (if any) to allergic asthma, and its molecular mechanism are not well understood. In this study, we report statistical analyses of degranulation assays performed in 68 control and 61 asthmatic subjects that establish higher basal and anti-IgE-stimulated basophil degranulation among the asthmatics. Remarkably, 28% of the control group and 13% of the asthmatic group were nonreleasers for all or part of our 4-year long study and cycling between the releaser and nonreleaser phenotypes occurred at least once in blood basophils from 8 (of 8) asthmatic and 16 (of 23) control donors. Microarray analysis showed that basal gene expression was generally lower in nonreleaser than releaser basophils. In releaser cells, FcεRI cross-linking up-regulated >200 genes, including genes encoding receptors (the FcεRI α and β subunits, the histamine 4 receptor, the chemokine (C-C motif) receptor 1), signaling proteins (Lyn), chemokines (IL-8, RANTES, MIP-1α, and MIP-1β) and transcription factors (early growth response-1, early growth response-3, and AP-1). FcεRI cross-linking induced fewer, and quite distinct, transcriptional responses in nonreleaser cells. We conclude that “nonreleaser” and “cycler” basophils represent a distinct and reversible natural phenotype. Although histamine is more readily released from basophils isolated from asthmatics than controls, the presence of nonreleaser basophils does not rule out the diagnosis of asthma.

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Syk and pTyr'd: Signaling through the B cell antigen receptor

Geahlen

2009

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

151

208

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The B cell receptor (BCR) transduces antigen binding into alterations in the activity of intracellular signaling pathways through its ability to recruit and activate the cytoplasmic protein-tyrosine kinase Syk. The recruitment of Syk to the receptor, its activation and its subsequent interactions with downstream effectors are all regulated by its phosphorylation on tyrosine. This review discusses our current understanding of how this phosphorylation regulates the activity of Syk and its participation in signaling through the BCR.

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Proteasome-dependent regulation of Syk tyrosine kinase levels in human basophils

Cited by 24 publications

References 29 publications

The Adaptor Molecule CIN85 Regulates Syk Tyrosine Kinase Level by Activating the Ubiquitin-Proteasome Degradation Pathway

The Adaptor Molecule CIN85 Regulates Syk Tyrosine Kinase Level by Activating the Ubiquitin-Proteasome Degradation Pathway

Histamine Release from the Basophils of Control and Asthmatic Subjects and a Comparison of Gene Expression between “Releaser” and “Nonreleaser” Basophils

Syk and pTyr'd: Signaling through the B cell antigen receptor

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