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Adapter molecules are multidomain proteins lacking intrinsic catalytic activity, functioning instead by nucleating molecular complexes during signal transduction. The SLP-76 family of adapters includes SH2 domain-containing leukocyte phosphoprotein of 76kDa (SLP-76), B cell linker protein (BLNK), and cytokine-dependent hematopoietic cell linker (Clnk). These proteins are critical for integration of numerous signaling cascades downstream of immunotyrosine-based activation motif (ITAM)-bearing receptors and integrins in diverse hematopoietic cell types. Mutations in genes encoding SLP-76 family adapters result in severe phenotypes, underscoring the critical role these proteins play in cellular development and function by directing formation of signaling complexes in a temporally- and spatially-specific manner.
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http://dx.doi.org/10.1016/j.smim.2004.08.018 | DOI Listing |
Eur J Immunol
February 2025
Technion-Israel Institute of Technology, Rappaport Faculty of Medicine, Haifa, Israel.
Thymocyte β-selection and positive-selection depend on TCR signaling via the immune adaptors SLP-76 and LAT. Gads bridges the recruitment of SLP-76 to LAT, yet is not required for the maturation of single positive (SP) thymocytes. To illuminate this paradox, we performed tamoxifen-induced ablation of Gads (Gads), accompanied by the expression of tdTomato, and compared the development of Gads-expressing (Tom) and Gads-ablated (Tom) thymocytes within the same mouse.
View Article and Find Full Text PDFProtein Expr Purif
May 2025
Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. Electronic address:
An early step in the activation of T cells via the T cell antigen receptor is the phosphorylation and activation of phospholipase C-γ1 (PLC-γ1) by the TEC family tyrosine kinase, interleukin-2 (IL-2) inducible T cell kinase (ITK). PLC-γ1 activation occurs within a multi-protein complex comprised of the enzymes ITK, PLC-γ1, and VAV, and the adapter molecules, LAT, Gads, SLP-76, and NCK. Studies of ITK activation and the role of this heptameric complex in regulating ITK activation and function have not been possible due to the lack of success in the expression and purification of full-length, monomeric ITK protein.
View Article and Find Full Text PDFNature
January 2024
Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
Bioorg Chem
November 2023
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address:
Despite immune checkpoint inhibitors' tremendous success in the treatment of tumors, the moderate response rate limits their widespread use. Hematopoietic progenitor kinase 1 (HPK1) is served as an essential negative regulator of T-cell receptor, which has been identified as a promising target for enhancing antitumor immunity. However, the development of a selective HPK1 inhibitor is still challenging.
View Article and Find Full Text PDFBioorg Chem
October 2023
Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, China; Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College. Electronic address:
Hematopoietic progenitor kinase 1 (HPK1), a member of the mitogen-activated protein kinase (MAP4K) family, is a serine/threonine (SER/THR) kinase and has been demonstrated as a negative regulator of T cell receptor signaling. Targeting HPK1 has been considered as an attractive therapeutic strategy for immune-oncology. Here, we describe the discovery and structure-activity relationship (SAR) of potent HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!