PMID- 10037717
OWN - NLM
STAT- MEDLINE
DCOM- 19990330
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 10
DP  - 1999 Mar 5
TI  - Tyrosine 319, a newly identified phosphorylation site of ZAP-70, plays a critical
      role in T cell antigen receptor signaling.
PG  - 6285-94
AB  - Following T cell antigen receptor (TCR) engagement, the protein tyrosine kinase
      (PTK) ZAP-70 is rapidly phosphorylated on several tyrosine residues, presumably
      by two mechanisms: an autophosphorylation and a trans-phosphorylation by the
      Src-family PTK Lck. These events have been implicated in both positive and
      negative regulation of ZAP-70 activity and in coupling this PTK to downstream
      signaling pathways in T cells. We show here that Tyr315 and Tyr319 in the
      interdomain B of ZAP-70 are autophosphorylated in vitro and become phosphorylated
      in vivo upon TCR triggering. Moreover, by mutational analysis, we demonstrate
      that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 
      function. Indeed, overexpression in Jurkat cells and in a murine T cell hybridoma
      of a ZAP-70 mutant in which Tyr319 was replaced by phenylalanine (ZAP-70-Y319F)
      dramatically impaired anti-TCR-induced activation of the nuclear factor of
      activated T cells and interleukin-2 production, respectively. Surprisingly, an
      analogous mutation of Tyr315 had little or no effect. The inhibitory effect of
      ZAP-70-Y319F correlated with a substantial loss of its activation-induced
      tyrosine phosphorylation and up-regulation of catalytic activity, as well as with
      a decreased in vivo capacity to phosphorylate known ZAP-70 substrates, such as
      SLP-76 and LAT. Collectively, our data reveal the pivotal role of Tyr319
      phosphorylation in the positive regulation of ZAP-70 and in TCR-mediated
      signaling.
FAU - Di Bartolo, V
AU  - Di Bartolo V
AD  - Molecular Immunology Unit, Department of Immunology, Institut Pasteur, 25 Rue du 
      Docteur Roux, 75724 Paris Cedex 15, France.
FAU - Mege, D
AU  - Mege D
FAU - Germain, V
AU  - Germain V
FAU - Pelosi, M
AU  - Pelosi M
FAU - Dufour, E
AU  - Dufour E
FAU - Michel, F
AU  - Michel F
FAU - Magistrelli, G
AU  - Magistrelli G
FAU - Isacchi, A
AU  - Isacchi A
FAU - Acuto, O
AU  - Acuto O
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (ZAP-70 Protein-Tyrosine Kinase)
RN  - EC 2.7.10.2 (ZAP70 protein, human)
SB  - IM
MH  - Amino Acid Sequence
MH  - Humans
MH  - Jurkat Cells
MH  - Molecular Sequence Data
MH  - Phosphorylation
MH  - Protein-Tyrosine Kinases/chemistry/*immunology
MH  - Receptors, Antigen, T-Cell/chemistry/*immunology
MH  - Signal Transduction/*immunology
MH  - T-Lymphocytes/*immunology
MH  - Tyrosine/chemistry/immunology
MH  - ZAP-70 Protein-Tyrosine Kinase
EDAT- 1999/02/26 00:00
MHDA- 1999/02/26 00:01
CRDT- 1999/02/26 00:00
PHST- 1999/02/26 00:00 [pubmed]
PHST- 1999/02/26 00:01 [medline]
PHST- 1999/02/26 00:00 [entrez]
AID - 10.1074/jbc.274.10.6285 [doi]
AID - S0021-9258(19)87586-5 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Mar 5;274(10):6285-94. doi: 10.1074/jbc.274.10.6285.