The Adhesion- and Degranulation-Promoting Adaptor Protein and Its Role in the Modulation of Experimental Autoimmune Encephalomyelitis

Engelmann, Swen; Togni, Mauro; Kliche, Stefanie; Reinhold, Dirk; Schraven, Burkhart; Reinhold, Annegret

doi:10.1615/critrevimmunol.2014012162

Cited by 8 publications

(10 citation statements)

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“…Only a handful of studies have attempted to investigate ADAP's role in human patients, but some correlation between ADAP expression or integrity with hemostastic or immune deficiency has been identified, thereby in part substantiating previous mouse studies (Engelmann et al 2015). The most revealing thus far have been two studies of patients of Middle Eastern descent from consanguineous families, exhibiting petechial rashes accompanied by a bleeding tendency.…”

Section: Adap Relevance To Human Patients and In Disease Modelsmentioning

confidence: 68%

“…Another major milestone was achieved with the generation of chimeric and knockout ADAP mice (ADAP À/À ) by Griffiths et al and Peterson et al and helped resolve some of the controversies related to ADAP function that had surfaced in studies with cell lines (Peterson 2003). In recent years, the elucidation of new ADAP domains and interaction partners has expanded the repertoire of functions attributed to ADAP that span from actin-regulatory roles in lymphocytes, macrophages, and platelets to regulation of mast cell degranulation, T cell proliferation, thymopoiesis, osteoclastogenesis, eosinophil survival, and integrin regulation (Engelmann et al 2015;Wang and Rudd 2008).…”

Section: Historical Backgroundmentioning

confidence: 99%

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Adap

Kasirer-Friede¹

2016

Encyclopedia of Signaling Molecules

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Section: Adap Relevance To Human Patients and In Disease Modelsmentioning

confidence: 68%

Section: Historical Backgroundmentioning

confidence: 99%

Adap

Kasirer-Friede¹

2016

Encyclopedia of Signaling Molecules

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“…The role of ADAP in other myeloid cells like mast cells, monocytes and macrophages remains largely unknown. ADAP-deficiency in microglia, the CNS-resident macrophage population does not influence microglia function such as NO production and cytokine release (14). Limited data are available about the role of ADAP in dendritic cells (DC).…”

Section: Introductionmentioning

confidence: 99%

Immune Cell-Type Specific Ablation of Adapter Protein ADAP Differentially Modulates EAE

et al. 2019

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The cytosolic adhesion and degranulation-promoting adapter protein ADAP is expressed in various hematopoietic cells including T cells, NK cells, myeloid cells, and platelets but absent in mature B cells. The role of ADAP in T cell activation, proliferation and integrin activation is well-accepted. We previously demonstrated that conventional ADAP knockout mice show a significantly attenuated course of experimental autoimmune encephalomyelitis (EAE). To dissect the impact of different ADAP expressing cell populations on the reduced EAE severity, here, we generated lineage-specific conditional knockout mice. ADAP was deleted in T cells, myeloid cells, NK cells and platelets, respectively. Specific loss of ADAP was confirmed on the protein level. Detailed immunophenotyping was performed to assess the consequence of deletion of ADAP with regard to the maturation and distribution of immune cells in primary and secondary lymphoid organs. The analysis showed equivalent results as for conventional ADAP knockout mice: impaired thymocyte development in ADAPfl/fl Lck-Cre mice, normal NK cell and myeloid cell distribution in ADAPfl/fl NKp46-Cre mice and ADAPfl/fl LysM-Cre mice, respectively as well as thrombocytopenia in ADAPfl/fl PF4-Cre mice. Active EAE was induced in these animals by immunization with the myelin oligodendrocyte glycoprotein35−55 peptide. The clinical course of EAE was significantly milder in mice with loss of ADAP in T cells, myeloid cells and NK cells compared to ADAP-sufficient control littermates. Surprisingly, specific deletion of ADAP in platelets resulted in a more exacerbated disease. These data show that T cell-independent as well as T cell-dependent mechanisms are responsible for the complex phenotype observed in conventional ADAP knockout mice.

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“…The adhesion and degranulation promoting adapter protein (ADAP) may be a common regulatory factor in these processes. ADAP is expressed in various hematopoietic cells including T-cells, platelets, mast cells, dendritic cells, natural killer cells, granulocytes, monocytes, macrophages (Wang and Rudd, 2008 ; Witte et al, 2012 ) and microglia (Engelmann et al, 2015 ), but public databases suggest that ADAP may also be expressed in neuronal cells during development and adulthood 1 .…”

Section: Introductionmentioning

confidence: 99%

“…ADAP protein occurs in two isoforms with molecular weights of 120 kDa and 130 kDa, without discernable enzymatic or transcriptional activity (Wang and Rudd, 2008 ). It contains a proline-rich region, several tyrosine-based signaling motifs, two helical SH3 domains, and an Ena/VASP binding motif to mediate protein-protein and protein-lipids interactions (Peterson, 2003 ; Wang and Rudd, 2008 ; Witte et al, 2012 ; Engelmann et al, 2015 ). It serves as a hub for the association of additional adaptor proteins, Ena/VASP proteins and kinases in T-cells, thereby facilitating T-cell activation, differentiation and adhesion (Peterson, 2003 ; Zhang and Wang, 2012 ; Witte et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Integrin Activation Through the Hematopoietic Adapter Molecule ADAP Regulates Dendritic Development of Hippocampal Neurons

Thiere

Kliche

Müller

et al. 2016

Front. Mol. Neurosci.

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Integrin-mediated cell adhesion and signaling is of critical importance for neuronal differentiation. Recent evidence suggests that an “inside-out” activation of β1-integrin, similar to that observed in hematopoietic cells, contributes to the growth and branching of dendrites. In this study, we investigated the role of the hematopoietic adaptor protein adhesion and degranulation promoting adapter protein (ADAP) in these processes. We demonstrate the expression of ADAP in the developing and adult nervous hippocampus, and in outgrowing dendrites of primary hippocampal neurons. We further show that ADAP occurs in a complex with another adaptor protein signal-transducing kinase-associated phosphoprotein-homolog (SKAP-HOM), with the Rap1 effector protein RAPL and the Hippo kinase macrophage-stimulating 1 (MST1), resembling an ADAP/SKAP module that has been previously described in T-cells and is critically involved in “inside-out” activation of integrins. Knock down of ADAP resulted in reduced expression of activated β1-integrin on dendrites. It furthermore reduced the differentiation of developing neurons, as indicated by reduced dendrite growth and decreased expression of the dendritic marker microtubule-associated protein 2 (MAP2). Our data suggest that an ADAP-dependent integrin-activation similar to that described in hematopoietic cells contributes to the differentiation of neuronal cells.

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The Adhesion- and Degranulation-Promoting Adaptor Protein and Its Role in the Modulation of Experimental Autoimmune Encephalomyelitis

Cited by 8 publications

References 0 publications

Adap

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Immune Cell-Type Specific Ablation of Adapter Protein ADAP Differentially Modulates EAE

Integrin Activation Through the Hematopoietic Adapter Molecule ADAP Regulates Dendritic Development of Hippocampal Neurons

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