Research Repository

Activated Cdc42-Associated kinase 1 (ACK1) binds the sterile - Motif (SAM) domain of the adaptor SLP-76 and phosphorylates proximal tyrosines

Thaker, YR and Recino, A and Raab, M and Jabeen, A and Wallberg, M and Fernandez, N and Rudd, CE (2017) 'Activated Cdc42-Associated kinase 1 (ACK1) binds the sterile - Motif (SAM) domain of the adaptor SLP-76 and phosphorylates proximal tyrosines.' Journal of Biological Chemistry, 292 (15). 6281 - 6290. ISSN 0021-9258

J. Biol. Chem.-2017-Thaker-6281-90.pdf - Published Version
Available under License Creative Commons Attribution.

Download (2MB) | Preview


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 identifiedSAMdomain-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
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Jim Jamieson
Date Deposited: 26 May 2017 13:07
Last Modified: 22 Jun 2021 19:15

Actions (login required)

View Item View Item