Leupaxin Negatively Regulates B Cell Receptor Signaling

Chew, Valerie; Lam, Kong-Peng

doi:10.1074/jbc.m704625200

Cited by 24 publications

(28 citation statements)

References 56 publications

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“…23,24,[60][61][62][63] In addition, we LPXN was reported to be phosphorylated only on Y72 upon B-cell antigen receptor stimulation in A20 mouse B lymphoma cells. 43 In contrast, our data showed that LPXN is phosphorylated on Y22, 62 and 72 upon GRPr activation in a fibroblast model system. The difference of LPXN tyrosine phosphorylated residues in B cells and adhesive cells might result from Fig.…”

Section: Discussioncontrasting

confidence: 53%

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Leupaxin is similar to paxillin in focal adhesion targeting and tyrosine phosphorylation but has distinct roles in cell adhesion and spreading

Chen

Kroog

2010

Cell Adhesion & Migration

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Section: Discussioncontrasting

confidence: 53%

“…[40][41][42] Y72 was reported to be phosphorylated by Lyn kinase in transfected 293T cells and in A20 B cells upon B cell antigen receptor stimulation. 43 There are three candidate Tyr phosphorylation sites in the LD domains: Y22, Y62 and Y72 (Fig. 3A).…”

Section: Resultsmentioning

confidence: 99%

Leupaxin is similar to paxillin in focal adhesion targeting and tyrosine phosphorylation but has distinct roles in cell adhesion and spreading

Chen

Kroog

2010

Cell Adhesion & Migration

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“…It is possible that other proteins compensate for paxillin knockdown or that paxillin plays a larger regulatory role in other stimulated cellular responses, such as cytokine production. In this regard, leupaxin (a member of the paxillin family of adaptor proteins) recently was shown to regulate cytokine production resulting from B cell receptor signaling (26). Paxillin knockdown in RBL cells did not detectably affect F-actin coredistribution with clustered IgE-Fc RI on patterned bilayers, indicating that other proteins are also involved in these linkages, and these may have other regulatory effects.…”

Section: Discussionmentioning

confidence: 99%

“…Paxillin is tyrosine-phosphorylated after antigen activation in RBL mast cells (7) and has been found to interact with Lyn kinase in this and several other cell types (8,25,26), suggesting that paxillin is one of the proteins that provides a link to vinculin, talin, and thereby to the actin cytoskeleton.…”

Section: Discussionmentioning

confidence: 99%

Focal adhesion proteins connect IgE receptors to the cytoskeleton as revealed by micropatterned ligand arrays

Torres

Vasudevan

Holowka

et al. 2008

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

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Patterned surfaces that present specific ligands in spatially defined arrays are used to examine structural linkages between clustered IgE receptors (IgE-Fc RI) and the cytoskeleton in rat basophilic leukemia (RBL) mast cells. We showed with fluorescence microscopy that cytoskeletal F-actin concentrates in the same regions as cell surface IgE-Fc RI that bind to the micrometer-size patterned ligands. However, the proteins mediating these cytoskeletal connections and their functional relevance were not known. We now show that whereas the adaptor proteins ezrin and moesin do not detectably concentrate with the array of clustered IgE-Fc RI, focal adhesion proteins vinculin, paxillin, and talin, which are known to link F-actin with integrins, accumulate in these regions on the same time scale as F-actin. Moreover, colocalization of these focal adhesion proteins with clustered IgE-Fc RI is enhanced after addition of fibronectin-RGD peptides. Significantly, the most prominent rat basophilic leukemia cell integrin (␣5) avoids the patterned regions occupied by the ligands and associates preferentially with exposed regions of the silicon substrate. Thus, spatial separation provided by the patterned surface reveals that particular focal adhesion proteins, which connect to the actin cytoskeleton, associate with ligand-cross-linked IgE-Fc RI, independently of integrins. We investigated the functional role of one of these proteins, paxillin, in IgE-Fc RI-mediated signaling by using small interfering RNA. From these results, we determine that paxillin reduces stimulated phosphorylation of the Fc RI ␤ subunit but enhances stimulated Ca 2؉ release from intracellular stores. The results suggest that paxillin associated with clustered IgE-Fc RI has a net positive effect on Fc RI signaling.FceRI ͉ Lyn ͉ nanobiotechnology ͉ paxillin ͉ supported lipid bilayers C ells have evolved to respond to their chemical and physical environment. Chemical stimulants in the form of soluble or surface-bound ligands are recognized by specific cell surface receptors, and physical cues are sensed by integrins that bind to extracellular matrix proteins on surrounding substrates (1). Cross-talk between intracellular signaling pathways that are initiated by integrins and by ligand receptors has been clearly demonstrated, although spatial aspects of these processes have not been defined. Surfaces patterned on the micrometer scale offer the opportunity to separate regions that bind integrins from those that present ligands to cell surface receptors and thereby delineate respective cytoskeletal connections.The subject of our study is the IgE receptor (Fc RI), which is a member of the family of multisubunit immune recognition receptors that includes antigen receptors on B cells and T cells. This family of receptors has conserved structural features and similarly initiates intracellular signaling in response to multivalent ligands (antigens) that activate cells by clustering cell surface receptors. Fc RI receptors are found primarily in mast cells and basophi...

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“…These effector proteins include components of the cytoskeleton, such as γ-actin (ACTG1) and α-tubulin (TUBA1B), as well as putative cytoskeleton regulators like Abelson protein tyrosine kinase 2 (ABL2) (22) and Leupaxin (LPXN) (23). The latter has also been described as a negative regulator of BCR signaling (24). We also identified significantly regulated phosphorylation of the Ikaros transcription factor family member Aiolos (IKZF3), which is known to be important for B-cell activation (25) and to be up-regulated in CLL (26).…”

Section: Bcr Signaling Network In Blmentioning

confidence: 99%

Elucidation of tonic and activated B-cell receptor signaling in Burkitt’s lymphoma provides insights into regulation of cell survival

Corso

Pan

Walter

et al. 2016

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

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Burkitt's lymphoma (BL) is a highly proliferative B-cell neoplasm and is treated with intensive chemotherapy that, because of its toxicity, is often not suitable for the elderly or for patients with endemic BL in developing countries. BL cell survival relies on signals transduced by B-cell antigen receptors (BCRs). However, tonic as well as activated BCR signaling networks and their relevance for targeted therapies in BL remain elusive. We have systematically characterized and compared tonic and activated BCR signaling in BL by quantitative phosphoproteomics to identify novel BCR effectors and potential drug targets. We identified and quantified ∼16,000 phospho-sites in BL cells. Among these sites, 909 were related to tonic BCR signaling, whereas 984 phospho-sites were regulated upon BCR engagement. The majority of the identified BCR signaling effectors have not been described in the context of B cells or lymphomas yet. Most of these newly identified BCR effectors are predicted to be involved in the regulation of kinases, transcription, and cytoskeleton dynamics. Although tonic and activated BCR signaling shared a considerable number of effector proteins, we identified distinct phosphorylation events in tonic BCR signaling. We investigated the functional relevance of some newly identified BCR effectors and show that ACTN4 and ARFGEF2, which have been described as regulators of membrane-trafficking and cytoskeletonrelated processes, respectively, are crucial for BL cell survival. Thus, this study provides a comprehensive dataset for tonic and activated BCR signaling and identifies effector proteins that may be relevant for BL cell survival and thus may help to develop new BL treatments.lymphoma | B-cell receptor | phosphoproteome | cancer biology

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Leupaxin Negatively Regulates B Cell Receptor Signaling

Cited by 24 publications

References 56 publications

Leupaxin is similar to paxillin in focal adhesion targeting and tyrosine phosphorylation but has distinct roles in cell adhesion and spreading

Leupaxin is similar to paxillin in focal adhesion targeting and tyrosine phosphorylation but has distinct roles in cell adhesion and spreading

Focal adhesion proteins connect IgE receptors to the cytoskeleton as revealed by micropatterned ligand arrays

Elucidation of tonic and activated B-cell receptor signaling in Burkitt’s lymphoma provides insights into regulation of cell survival

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