A5051723965- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Immunotherapy and Immune Responses
- Signaling Pathways in Disease
- Protein Kinase Regulation and GTPase Signaling
- Cell Adhesion Molecules Research
- Immunodeficiency and Autoimmune Disorders
- Ubiquitin and proteasome pathways
- Immune Response and Inflammation
- Blood disorders and treatments
- Glycosylation and Glycoproteins Research
- 14-3-3 protein interactions
- Chronic Lymphocytic Leukemia Research
- Monoclonal and Polyclonal Antibodies Research
- Chemokine receptors and signaling
- Fungal and yeast genetics research
- Macrophage Migration Inhibitory Factor
- Cancer-related gene regulation
- Academic Writing and Publishing
- Cell death mechanisms and regulation
- Viral-associated cancers and disorders
- Galectins and Cancer Biology
- Cancer Research and Treatments
- Cystic Fibrosis Research Advances
- Cellular transport and secretion
Technion – Israel Institute of Technology
2011-2025
Rappaport Family Institute for Research in the Medical Sciences
2006-2011
Israel Institute
2011
University of California, San Francisco
1998-2007
Howard Hughes Medical Institute
1998-2003
Hebrew University of Jerusalem
1993-1996
Activation of nonreceptor protein tyrosine kinases (PTKs) is essential for T cell receptor (TCR) responsiveness; however, the function individual PTK substrates often uncertain. A mutant line was isolated that lacked expression SLP-76 (SH2 domain–containing leukocyte 76 kilodaltons), a hematopoietically expressed adaptor and substrate. not required TCR-induced phosphorylation most proteins, but optimal activation phospholipase C-γ1 (PLC-γ1), as well Ras pathway activation. TCR-inducible gene...
AbstractSLP-76 is an adapter protein required for T-cell receptor (TCR) signaling. In particular, TCR-induced tyrosine phosphorylation and activation of phospholipase C-γ1 (PLC-γ1), the resultant TCR-inducible gene expression, depend on SLP-76. Nonetheless, mechanisms by which SLP-76 mediates PLC-γ1 are not well understood. We now demonstrate that directly interacts with Src homology 3 (SH3) domain PLC-γ1. Structure-function analysis revealed each previously defined protein-protein...
B cell linker protein (BLNK) is a SLP-76-related adaptor essential for signal transduction from the BCR. To identify components of BLNK-associated signaling pathways, we performed phosphorylation-dependent yeast two-hybrid analysis using BLNK probes. Here report that serine/threonine kinase hematopoietic progenitor 1 (HPK1), which activated upon antigen-receptor stimulation and has been implicated in regulation MAP interacts physically functionally with cells SLP-76 T cells. This interaction...
Abstract Engagement of the T cell with Ag on an APC results in a series immediate signaling events emanating from stimulation TCR. These include induced phosphorylation number cellular proteins subsequent increase intracellular calcium and restructuring microtubule actin cytoskeleton within cell. This culminates polarization cell’s secretory apparatus toward engaging APC, allowing to direct secretion cytokines appropriate APC. can be monitored by analyzing position microtubule-organizing...
ITK (IL-2-inducible T cell kinase), a Tec family protein tyrosine kinase (PTK), is one of three PTKs required for antigen receptor (TCR)-induced activation phospholipase C-gamma1 (PLC-gamma1). Like Src and Abl PTKs, adopts an inactive, "closed" conformation, its conversion to the active conformation not well understood, nor have direct substrates been identified. In side-by-side comparison ZAP-70 (zeta chain-associated 70 kDa), efficiently phosphorylated Y(783) Y(775) PLC-gamma1, two...
Antigen recognition within immunological synapses triggers and sustains T cell activation by nucleating protein microclusters that gather receptors (TCRs), kinases, adaptors. Dissipation of these results in signal termination, but how this process is regulated unclear. In paper, we reveal release the adaptors SLP76 GADS from signaling induced serine/threonine kinase HPK1 phosphorylation plays a major role process. We found was recruited into triggered their dissipation inducing...
The mitogen-activated protein kinase cascade of the Saccharomyces cerevisiae pheromone response pathway is organized on Ste5 protein, which binds each kinases prior to signaling. In this study, a structure–function analysis deletion mutants uncovered new functional domains and revealed that dimerizes during course normal signal transduction. Dimerization, mediated by two regions in N-terminal half Ste5, was first suggested intragenic complementation between pairs nonfunctional confirmed...
In circulating lymphocytes, the VLA-4 integrin preexists in multiple affinity states that mediate spontaneous tethering, rolling, and arrest on its endothelial ligand, vascular cell adhesion molecule-1 (VCAM-1). The regulation function of lymphocytes has never been elucidated. We show here p56lck, major Src kinase T cells, is a key regulator high VLA-4. This essential for rapid development firm resting cells to VCAM-1 their extracellular matrix fibronectin. Lck-regulated does not require...
The Paks (p21-activated kinases) Pak1, Pak2 and Pak3 are among the most studied effectors of Rho-family GTPases, Rac, Cdc42 (cell division cycle 42) Chp (Cdc42 homologous protein). Pak kinases influence a variety cellular functions, but process down-regulation, following activation, is poorly understood. In present study, we describe for first time negative-inhibitory loop generated by small Rho-GTPases Chp, resulting in Pak1 inhibition. Upon overexpression unexpectedly observed T-cell...
The T cell receptor (TCR) signaling pathway is an ensemble of numerous proteins that are crucial for adequate immune response. Disruption any protein involved in this leads to severe immunodeficiency and unfavorable clinical outcomes. Here, we describe infant with who was found have novel biallelic mutations SLP76. SLP76 a key TCR other hematopoietic pathways. Previous studies were performed using Jurkat-derived human leukemic lines SLP76-deficient mice. Our current study links gene, the...
Phospholipase C-γ1 (PLC-γ1) activation depends on a heterotrimeric complex of adaptor proteins composed LAT, Gads, and SLP-76. Upon T cell receptor stimulation, portion PLC-γ1 is recruited to detergent-resistant membrane fraction known as the glycosphingolipid-enriched microdomains (GEMs), or lipid rafts, which LAT constitutively localized. In addition GEM recruitment depended SLP-76, and, in particular, required Gads-binding domain The N-terminal tyrosine phosphorylation sites P-I region...
Thymocyte β-selection and positive-selection depend on TCR signaling via the immune adaptors SLP-76 LAT. Gads bridges recruitment of to LAT, yet is not required for maturation single positive (SP) thymocytes. To illuminate this paradox, we performed tamoxifen-induced ablation (GadsiKO), accompanied by expression tdTomato, compared development Gads-expressing (Tom-) Gads-ablated (Tom+) thymocytes within same mouse. GadsiKO exhibited impaired β- positive-selection, δ-selection was affected....
Engagement of the TCR or chemokine receptors such as CXCR4 induces adhesion and migration T cells via so-called inside-out signaling pathways. The molecular processes underlying events are yet not completely understood. In this study, we show that TCR- CXCR4-mediated activation integrins critically depends on membrane recruitment adhesion- degranulation-promoting adapter protein (ADAP)/Src kinase-associated phosphoprotein 55 kDa (SKAP55)/Rap1-interacting (RIAM)/Rap1 module. We further...
Pak (p21-activated kinase) serine/threonine kinases have been shown to mediate directional sensing of chemokine gradients. We hypothesized that may also chemokine-induced shape changes, facilitate leucocyte chemotaxis through restrictive barriers, such as the extracellular matrix. A potent inhibitor, Paki, was characterized and used probe role Pak-family in SDF-1α (stromal-cell derived factor-1α/CXCL12)-induced a T cell model. Paki potently inhibited SDF-1α-induced activation by bivalent...
SLP-76 forms part of a hematopoietic-specific adaptor protein complex, and is absolutely required for T cell development activation. receptor (TCR)-induced activation phospholipase C-gamma1 (PLC-gamma1) depends on three features SLP-76: the N-terminal tyrosine phosphorylation sites, Gads-binding site, an intervening sequence, denoted P-I region, which binds to SH3 domain PLC-gamma1 (SH3(PLC)) via low affinity interaction. Despite extensive research, mechanism whereby regulates remains...
Constitutive dimerization of an adaptor molecule enables it to selectively amplify signaling by binding cooperatively complexes downstream antigen receptors.
The costimulatory receptor CD28 synergizes with the TCR to promote IL-2 production, cell survival, and proliferation; yet obligatory interdependence of signaling is not well understood. Upon stimulation, Gads, a Grb2-family adaptor, bridges interaction two additional adaptors, LAT SLP-76, form TCR-induced effector complex. SLP-76 binds Tec-family tyrosine kinase, Itk, which phosphorylates Y173 PLC-γ1 Y783. In this study, we identified TCR-inducible, Itk-mediated phosphorylation Gads Y45 in...