Thaker, Youg R and Recino, Asha and Raab, Monika and Jabeen, Asma and Wallberg, Maja and Fernandez, Nelson and Rudd, Christopher E (2017) Activated Cdc42-associated kinase 1 (ACK1) binds the sterile α motif (SAM) domain of the adaptor SLP-76 and phosphorylates proximal tyrosines. Journal of Biological Chemistry, 292 (15). pp. 6281-6290. DOI https://doi.org/10.1074/jbc.m116.759555
Thaker, Youg R and Recino, Asha and Raab, Monika and Jabeen, Asma and Wallberg, Maja and Fernandez, Nelson and Rudd, Christopher E (2017) Activated Cdc42-associated kinase 1 (ACK1) binds the sterile α motif (SAM) domain of the adaptor SLP-76 and phosphorylates proximal tyrosines. Journal of Biological Chemistry, 292 (15). pp. 6281-6290. DOI https://doi.org/10.1074/jbc.m116.759555
Thaker, Youg R and Recino, Asha and Raab, Monika and Jabeen, Asma and Wallberg, Maja and Fernandez, Nelson and Rudd, Christopher E (2017) Activated Cdc42-associated kinase 1 (ACK1) binds the sterile α motif (SAM) domain of the adaptor SLP-76 and phosphorylates proximal tyrosines. Journal of Biological Chemistry, 292 (15). pp. 6281-6290. DOI https://doi.org/10.1074/jbc.m116.759555
Abstract
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.
Item Type: | Article |
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Uncontrolled Keywords: | T-Lymphocytes; Jurkat Cells; Animals; Humans; Mice; Tyrosine; Adaptor Proteins, Signal Transducing; Receptors, Antigen, T-Cell; Phosphoproteins; Amino Acid Substitution; Lymphocyte Activation; Amino Acid Motifs; Phosphorylation; Mutation, Missense; Protein-Tyrosine Kinases; Protein Domains |
Subjects: | Q Science > QH Natural history > QH301 Biology |
Divisions: | Faculty of Science and Health Faculty of Science and Health > Life Sciences, School of |
SWORD Depositor: | Unnamed user with email elements@essex.ac.uk |
Depositing User: | Unnamed user with email elements@essex.ac.uk |
Date Deposited: | 26 May 2017 13:07 |
Last Modified: | 30 Oct 2024 20:27 |
URI: | http://repository.essex.ac.uk/id/eprint/19731 |
Available files
Filename: J. Biol. Chem.-2017-Thaker-6281-90.pdf
Licence: Creative Commons: Attribution 3.0