Activated Cdc42-associated kinase 1 (ACK1) binds the sterile α motif (SAM) domain of the adaptor SLP-76 and phosphorylates proximal tyrosines
| Autor: | Nelson Fernandez, Christopher E. Rudd, Asha Recino, Youg Raj Thaker, Asma Jabeen, Maja Wallberg, Monika Raab |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
T-Lymphocytes Amino Acid Motifs Mutation Missense Receptors Antigen T-Cell non-receptor tyrosine kinase (nRTK) Lymphocyte Activation Biochemistry SH3 domain Receptor tyrosine kinase immunology Jurkat Cells Mice 03 medical and health sciences Protein Domains Calcium flux Animals Humans cell signaling Protein phosphorylation Phosphorylation sterile α motif (SAM) Tyrosine Molecular Biology Adaptor Proteins Signal Transducing biology T-cell receptor cluster of differentiation 4 (CD4) T cell Cell Biology Protein-Tyrosine Kinases Phosphoproteins Molecular biology protein phosphorylation 3. Good health Cell biology 030104 developmental biology Amino Acid Substitution biology.protein Tyrosine kinase Signal Transduction Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Popis: | The adaptor protein Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) plays a crucial role in T cell activation by linking antigen receptor (T cell receptor, TCR) signals to downstream pathways. At its N terminus, SLP-76 has three key tyrosines (Tyr-113, Tyr-128, and Tyr-145, “3Y”) as well as a sterile α motif (SAM) domain whose function is unclear. We showed previously that the SAM domain has two binding regions that mediate dimer and oligomer formation. In this study, we have identified SAM domain-carrying non-receptor tyrosine kinase, activated Cdc42-associated tyrosine kinase 1 (ACK1; also known as Tnk2, tyrosine kinase non-receptor 2) as a novel binding partner of SLP-76. Co-precipitation, laser-scanning confocal microscopy, and in situ proximity analysis confirmed the binding of ACK1 to SLP-76. Further, the interaction was induced in response to the anti-TCR ligation and abrogated by the deletion of SLP-76 SAM domain (ΔSAM) or mutation of Tyr-113, Tyr-128, and Tyr-145 to phenylalanine (3Y3F). ACK1 induced phosphorylation of the SLP-76 N-terminal tyrosines (3Y) dependent on the SAM domain. Further, ACK1 promoted calcium flux and NFAT-AP1 promoter activity and decreased the motility of murine CD4+ primary T cells on ICAM-1-coated plates, an event reversed by a small molecule inhibitor of ACK1 (AIM-100). These findings identify ACK1 as a novel SLP-76-associated protein-tyrosine kinase that modulates early activation events in T cells. |
| Databáze: | OpenAIRE |
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