Src-like adaptor protein (SLAP) regulates B cell receptor levels in a c-Cbl-dependent manner

Dragone, Leonard L.; Myers, Margaret D.; White, C.A.; Gadwal, Shyam; Sosinowski, Tomasz; Gu, Hua; Weiss, Arthur

doi:10.1073/pnas.0608965103

Cited by 38 publications

(53 citation statements)

References 39 publications

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“…Cbl proteins containing several protein modulatory regions and most notably a ring finger domain that functions as an E3 ligase in the ubiquitation and rapid down-regulation of various receptors including the EGF, PDGF, T and B cell receptors [82][83][84][85]. However, the insulin receptor does not undergo a rapid down-regulation process following ligand engagement in contrast to these other receptors.…”

Section: Insulin Signaling Leading To Glut4 Translocationmentioning

confidence: 99%

Ins (endocytosis) and outs (exocytosis) of GLUT4 trafficking

Hou

Pessin

2007

Current Opinion in Cell Biology

132

116

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SummaryGlucose transporter 4 (GLUT4) is the major insulin regulated glucose transporter expressed mainly in muscle and adipose tissue. GLUT4 is stored in a poorly characterized intracellular vesicular compartment and translocates to the cell surface in response to insulin stimulation resulting in increase glucose uptake. This process is essential for the maintenance of normal glucose homeostasis and involves a complex interplay of trafficking events and intracellular signaling cascades. Recent studies have identified sortilin as an essential element for the formation of GLUT4 storage vesicles during adipogenesis and GGA (Golgi-localized γ-ear-containing Arf-binding protein) as a key coat adaptor for the entry of newly synthesized GLUT4 into the specialized compartment. Insulinstimulated GLUT4 translocation from this compartment to the plasma membrane appears to require the Akt/protein kinase B substrate, termed AS160 (Akt Substrate of 160 kDa). In addition, the VPS9 domain-containing protein Gapex-5 in complex with CIP4 appears to function as a Rab31 guanylnucleotide exchange factor that is necessary for insulin-stimulated GLUT4 translocation. Here we attempt to summaries recent advances in GLUT4 vesicle biogenesis, intracellular trafficking and membrane fusion.

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Section: Insulin Signaling Leading To Glut4 Translocationmentioning

confidence: 99%

Ins (endocytosis) and outs (exocytosis) of GLUT4 trafficking

Hou

Pessin

2007

Current Opinion in Cell Biology

132

116

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“…SLAP and SLAP2 are expressed in many hematopoietic cell types and have a negative regulatory role in the regulation of TCR, BCR, and CSF-1R (8)(9)(10)(11)(12)(13)(14)(15)(16). Our previous studies showed a role for SLAP2 in CSF-1R signaling, leading us to examine whether SLAP and SLAP2 could be involved in the regulation of hematopoietic cytokine signaling and early myeloid differentiation.…”

Section: Bm-dcmentioning

confidence: 99%

“…TCR regulation by SLAP is important during development, because T cells from SLAP 2/2 mice display defects in the double-positive stage (CD4 + CD8 + ) of thymocyte development and not in peripheral T cells (9). Although SLAP and SLAP2 seem to play a role in T cell signaling, their expression is not limited to T cells; they are expressed in a variety of hematopoietic cell types, including B cells, mast cells, macrophages, and early progenitor cells (13)(14)(15)(16).…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

The Src-Like Adaptor Protein Regulates GM-CSFR Signaling and Monocytic Dendritic Cell Maturation

Liontos

Dissanayake

Ohashi

et al. 2011

The Journal of Immunology

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GM-CSF is an important cytokine involved in myeloid differentiation and inflammatory processes. Signaling through the GM-CSFR also plays a critical role in the generation of monocyte-derived dendritic cells (DC). In this article, we report that the Src-like adaptor protein (SLAP) functions as a negative regulator of the GM-CSFR. In bone marrow-derived DC (BM-DC) lacking SLAP and the closely related SLAP2, downregulation of GM-CSFRβ is impaired, leading to enhanced phosphorylation of Jak2 and prolonged activation of Akt and Erk1/2 in response to GM-CSF stimulation. Compared with wild-type bone marrow, SLAP/SLAP2−/− bone marrow gave rise to similar numbers of CD11c+ and CD11b+ DC, but SLAP/SLAP2−/− BM-DC failed to acquire high levels of MHC class II, CD80, and CD86, indicating an impairment in maturation. Furthermore, MHC class II expression in SLAP/SLAP2−/− BM-DC was rescued by decreasing GM-CSF concentration, suggesting that enhanced GM-CSF signaling mediates the block in maturation. In addition, SLAP/SLAP2−/− BM-DC produced less IL-12 and TNF-α in response to LPS compared with controls and failed to stimulate T cells in an MLR. Ag-specific T cell activation assays showed that SLAP/SLAP2−/− BM-DC were less robust at inducing IFN-γ secretion by DO11.10 T cells. These results indicated that SLAP-mediated GM-CSFR regulation is important for the generation of functionally mature monocytic DC.

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“…The Src-like adaptor protein (SLAP) (19) and the E3 ubiquitin ligase Cbl family proteins (20) have also been implicated in the regulation of BCR levels. SLAP and c-Cbl together were able to mediate BCR downmodulation (21), whereas Cbl-b and c-Cbl were required for efficient BCR internalization, although the functional relationship between SLAP and Cbl family proteins still remains obscure. Mice lacking c-Cbl and Cbl-b had elevated levels of serum IgM and anti-dsDNA Ab and developed autoimmunity as they aged (20).…”

mentioning

confidence: 99%

A Role for Lysosomal-Associated Protein Transmembrane 5 in the Negative Regulation of Surface B Cell Receptor Levels and B Cell Activation

Ouchida

Kurosaki

Wang

2010

The Journal of Immunology

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Mechanisms by which cell surface levels of the BCR are regulated remain largely unknown. We found that B cells lacking the lysosomal-associated protein transmembrane 5 (LAPTM5) expressed higher levels of cell surface BCR than did wild-type (WT) B cells after Ag stimulation in vitro and in vivo. In addition, LAPTM5-deficient mice contained an increased frequency of Ag-specific B cells and produced greater amounts of Abs than did WT mice after immunization with a T-dependent Ag. Adoptive transfer of LAPTM5-deficient B cells with WT T cells into RAG1-deficient mice revealed that the increased surface BCR levels and the enhanced B cell activation and Ab production were due to a B cell intrinsic defect. As they aged, the LAPTM5-deficient mice had increased titers of serum IgM and autoantibodies and immune complex deposition in the kidney. Immunofluorescent and biochemical analysis revealed that LAPTM5 physically interacted with the BCR complex and promoted its degradation in the lysosomal compartment in mouse B cells. These results demonstrate a role for LAPTM5 in the negative regulation of cell surface BCR levels and B cell activation.

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Src-like adaptor protein (SLAP) regulates B cell receptor levels in a c-Cbl-dependent manner

Cited by 38 publications

References 39 publications

Ins (endocytosis) and outs (exocytosis) of GLUT4 trafficking

Ins (endocytosis) and outs (exocytosis) of GLUT4 trafficking

The Src-Like Adaptor Protein Regulates GM-CSFR Signaling and Monocytic Dendritic Cell Maturation

A Role for Lysosomal-Associated Protein Transmembrane 5 in the Negative Regulation of Surface B Cell Receptor Levels and B Cell Activation

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