SHP-1 dephosphorylates 3BP2 and potentially downregulates 3BP2-mediated T cell antigen receptor signaling.
Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-1 (SHP-1) is a critical inhibitory regulator in T cell-receptor (TCR) signaling. However, the exact molecular mechanism underlying this is poorly defined, largely because the physiological substrates for SHP-1 in T cells remain elusive. In this study, we showed that adaptor protein 3BP2 serves as a binding protein and a physiological substrate of SHP-1. 3BP2 is phosphorylated on tyrosyl residue 448 in response to TCR activation, and the phosphorylation is required for T cell signalling, as indicated by transcriptional activation of nuclear factor activated in T cells (NFAT). Concurrently, phosphorylation of Tyr566 at the C-terminus of SHP-1 causes specific recruitment of 3BP2 to the phosphatase through the SH2 domain of the adaptor protein. This leads to efficient dephosphorylation of 3BP2 and thereby termination of T cell signaling. The study thus defines a novel function of the C-terminal segment of SHP-1 and reveals a new mechanism by which T cell signaling is regulated.
Yu
Zhenbao
Z
Health Sector, Biotechnology Research Institute, National Research Council of Canada, Montréal, Canada. zhenbao.yu@nrc.ca
Maoui
Meryem
M
Zhao
Zhizhuang J
ZJ
Li
Yang
Y
Shen
Shi-Hsiang
SH
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D020798:Two-Hybrid System Techniques; D018909:src Homology Domains / Q000187:drug effects / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; C109073:SH3BP2 protein, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D054645:Protein Phosphatase 1; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases