Regulation of In Vitro and In Vivo Immune Functions by the Cytosolic Adaptor Protein SKAP-HOM

Togni, Mauro; Swanson, Kenneth D.; Reimann, Sibylle; Kliche, Stefanie; Pearce, Andrew C.; Simeoni, Luca; Reinhold, Dirk; Wienands, Jürgen; Neel, Benjamin G.; Schraven, Burkhart; Gerber, Annegret

doi:10.1128/mcb.25.18.8052-8063.2005

Cited by 81 publications

(126 citation statements)

References 35 publications

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“…Our data implicate Bam32 as another PH domain target of PI3K involved in modulating the balance between GTPase activation and inactivation during B cell activation. Our results regarding Bam32 have similarities with data on Src kinase-associated phosphoprotein (SKAP) and SKAP-HOM adaptors, which are also PH domain proteins and were shown to regulate T cell or B cell adhesion, respectively (56)(57)(58). Interestingly, these molecules are thought to act by selectively modulating Rap activation (59, 60), whereas we find that Bam32 regulates Rac but not Rap (data not shown).…”

Section: Discussionsupporting

confidence: 45%

Bam32/DAPP1 Promotes B Cell Adhesion and Formation of Polarized Conjugates with T Cells

Al‐Alwan¹,

Hou²,

Zhang

et al. 2010

The Journal of Immunology

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B cell Ag receptors function in both signaling activation of Ag-specific cells and in collecting specific Ag for presentation to T lymphocytes. Signaling via PI3K is required for BCR-mediated activation and Ag presentation functions; however, the relevant downstream targets of PI3K in B cells are incompletely defined. In this study, we have investigated the roles of the PI3K effector molecule Bam32/DAPP1 in BCR signaling and BCR-mediated Ag presentation functions. In mouse primary B cells, Bam32 was required for efficient activation of the GTPase Rac1 and downstream signaling to JNK, but not activation of BLNK, phospholipase C γ2, or calcium responses. Consistent with a role of this adaptor in Rac-mediated cytoskeletal rearrangement, Bam32 was required for BCR-induced cell adhesion and spreading responses on ICAM-1 or fibronectin-coated surfaces. The function of Bam32 in promoting Rac activation and adhesion required tyrosine 139, a known site of phosphorylation by Lyn kinase. After BCR crosslinking by Ag, Bam32-deficient B cells are able to carry out the initial steps of Ag endocytosis and processing, but show diminished ability to form Ag-specific conjugates with T cells and polarize F-actin at the B-T interface. As a result, Bam32-deficient B cells were unable to efficiently activate Ag-specific T cells. Together, these results indicate that Bam32 serves to integrate PI3K and Src kinase signaling to promote Rac-dependent B cell adhesive interactions important for Ag presentation function.

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Section: Discussionsupporting

confidence: 45%

Bam32/DAPP1 Promotes B Cell Adhesion and Formation of Polarized Conjugates with T Cells

Al‐Alwan¹,

Hou²,

Zhang

et al. 2010

The Journal of Immunology

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“…In SKAP-HOM-deficient mice, B cell receptor-mediated proliferation is strongly attenuated, and adhesion of activated B cells to fibronectin as well as to ICAM-1 is strongly reduced (48). In addition, the loss of SKAP-HOM also results in a less severe clinical course of experimental autoimmune encephalomyelitis following immunization of mice with the encephalitogenic peptide of myelin oligodendrocyte glycoprotein.…”

Section: 48)mentioning

confidence: 80%

Substrate Specificity of Lymphoid-specific Tyrosine Phosphatase (Lyp) and Identification of Src Kinase-associated Protein of 55 kDa Homolog (SKAP-HOM) as a Lyp Substrate

Yu¹,

Chen²,

Zhang

et al. 2011

Journal of Biological Chemistry

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A missense single-nucleotide polymorphism in the gene encoding the lymphoid-specific tyrosine phosphatase (Lyp) has been identified as a causal factor in a wide spectrum of autoimmune diseases. Interestingly, the autoimmune-predisposing variant of Lyp appears to represent a gain-of-function mutation, implicating Lyp as an attractive target for the development of effective strategies for the treatment of many autoimmune disorders. Unfortunately, the precise biological functions of Lyp in signaling cascades and cellular physiology are poorly understood. Identification and characterization of Lyp substrates will help define the chain of molecular events coupling Lyp dysfunction to diseases. In the current study, we identified consensus sequence motifs for Lyp substrate recognition using an "inverse alanine scanning" combinatorial library approach. The intrinsic sequence specificity data led to the discovery and characterization of SKAP-HOM, a cytosolic adaptor protein required for proper activation of the immune system, as a bona fide Lyp substrate. To determine the molecular basis for Lyp substrate recognition, we solved crystal structures of Lyp in complex with the consensus peptide as well as the phosphopeptide derived from SKAP-HOM. Together with the biochemical data, the structures define the molecular determinants for Lyp substrate specificity and provide a solid foundation upon which novel therapeutics targeting Lyp can be developed for multiple autoimmune diseases.Protein-tyrosine phosphorylation-mediated signal transduction is essential for a wide range of eukaryotic functions, including cell proliferation, differentiation, migration, apoptosis, and the immune responses (1). This signaling mechanism is often dysregulated in human diseases, due to aberrant activity of the enzymes involved in the regulation of protein tyrosine phosphorylation status (1, 2). Thus, a comprehensive understanding of the physiological roles of protein tyrosine phosphorylation and how this process is abrogated in the pathogenesis of human diseases must necessarily include characterization of proteintyrosine phosphatases (PTPs), 4 in addition to protein-tyrosine kinases.The lymphoid-specific tyrosine phosphatase (Lyp) has garnered tremendous interest due to the observation that a missense C1858T single nucleotide polymorphism in the gene (PTPN22) encoding Lyp is associated with multiple autoimmune disorders, including type I diabetes (3), rheumatoid arthritis (4, 5), Graves disease (6), and systemic lupus erythematosus (7). Lyp expression is restricted to human T cells, B cells, and macrophages (8). Lyp exerts an inhibitory effect on the proximal T cell receptor signaling pathways, probably through dephosphorylation of the Lck and ZAP-70 kinases (9 -11). The C1858T single nucleotide polymorphism changes Arg 620 into a Trp within the first Pro-rich region in the C terminus of Lyp, leading to loss of Lyp binding to the Src homology 3 domain of the Src C-terminal kinase (Csk) (3, 4). Importantly, the autoimmune-predisposing variant of...

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“…Induction of EAE was performed as described earlier (32). Briefly, active EAE was induced by immunization with 200 mg MOG p35-55 emulsified in CFA (Sigma-Aldrich) containing 800 mg heat-killed Mycobacterium tuberculosis (Difco Laboratories).…”

Section: Eae Inductionmentioning

confidence: 99%

T Cell–Independent Modulation of Experimental Autoimmune Encephalomyelitis in ADAP-Deficient Mice

Engelmann

Togni

Thielitz

et al. 2013

The Journal of Immunology

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The adhesion- and degranulation-promoting adaptor protein (ADAP), expressed in T cells, myeloid cells, and platelets, is known to regulate receptor-mediated inside-out signaling leading to integrin activation and adhesion. In this study, we demonstrate that, upon induction of active experimental autoimmune encephalomyelitis (EAE) by immunization with the myelin oligodendrocyte glycoprotein35–55 peptide, ADAP-deficient mice developed a significantly milder clinical course of EAE and showed markedly less inflammatory infiltrates in the CNS than wild-type mice. Moreover, ADAP-deficient recipients failed to induce EAE after adoptive transfer of myelin oligodendrocyte glycoprotein–specific TCR-transgenic T cells (2D2 T cells). In addition, ex vivo fully activated 2D2 T cells induced significantly less severe EAE in ADAP-deficient recipients. The ameliorated disease in the absence of ADAP was not due to expansion or deletion of a particular T cell subset but rather because of a strong reduction of all inflammatory leukocyte populations invading the CNS. Monitoring the adoptively transferred 2D2 T cells over time demonstrated that they accumulated within the lymph nodes of ADAP-deficient hosts. Importantly, transfer of complete wild-type bone marrow or even bone marrow of 2D2 TCR–transgenic mice was unable to reconstitute EAE in the ADAP-deficient animals, indicating that the milder EAE was dependent on (a) radio-resistant nonhematopoietic cell population(s). Two-photon microscopy of lymph node explants revealed that adoptively transferred lymphocytes accumulated at lymphatic vessels in the lymph nodes of ADAP-deficient mice. Thus, our data identify a T cell–independent mechanism of EAE modulation in ADAP-deficient mice.

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Regulation of In Vitro and In Vivo Immune Functions by the Cytosolic Adaptor Protein SKAP-HOM

Cited by 81 publications

References 35 publications

Bam32/DAPP1 Promotes B Cell Adhesion and Formation of Polarized Conjugates with T Cells

Bam32/DAPP1 Promotes B Cell Adhesion and Formation of Polarized Conjugates with T Cells

Substrate Specificity of Lymphoid-specific Tyrosine Phosphatase (Lyp) and Identification of Src Kinase-associated Protein of 55 kDa Homolog (SKAP-HOM) as a Lyp Substrate

T Cell–Independent Modulation of Experimental Autoimmune Encephalomyelitis in ADAP-Deficient Mice

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