Regulation of the type 1 inositol 1,4,5-trisphosphate receptor by phosphorylation at tyrosine 353.
The inositol 1,4,5-trisphosphate receptor (IP3R) plays an essential role in Ca2+ signaling during lymphocyte activation. Engagement of the T cell or B cell receptor by antigen initiates a signal transduction cascade that leads to tyrosine phosphorylation of IP3R by Src family nonreceptor protein tyrosine kinases, including Fyn. However, the effect of tyrosine phosphorylation on the IP3R and subsequent Ca2+ release is poorly understood. We have identified tyrosine 353 (Tyr353) in the IP3-binding domain of type 1 IP3R (IP3R1) as a phosphorylation site for Fyn both in vitro and in vivo. We have developed a phosphoepitope-specific antibody and shown that IP3R1-Y353 becomes phosphorylated during T cell and B cell activation. Furthermore, tyrosine phosphorylation of IP3R1 increased IP3 binding at low IP3 concentrations (<10 nm). Using wild-type IP3R1 or an IP3R1-Y353F mutant that cannot be tyrosine phosphorylated at Tyr353 or expressed in IP3R-deficient DT40 B cells, we demonstrated that tyrosine phosphorylation of Tyr353 permits prolonged intracellular Ca2+ release during B cell activation. Taken together, these data suggest that one function of tyrosine phosphorylation of IP3R1-Y353 is to enhance Ca2+ signaling in lymphocytes by increasing the sensitivity of IP3R1 to activation by low levels of IP3.
Cui
Jie
J
Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Matkovich
Scot J
SJ
deSouza
Nikhil
N
Li
Suzhao
S
Rosemblit
Nora
N
Marks
Andrew R
AR
D001665:Binding Sites; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000378:metabolism; D014443:Tyrosine
D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D014443:Tyrosine