CD19 regulates Src family protein tyrosine kinase activation in B lymphocytes through processive amplification.
CD19 regulates constitutive and antigen receptor-induced signaling thresholds in B lymphocytes through its unique cytoplasmic domain. Herein, we demonstrate a novel molecular mechanism where interactions between CD19 and Lyn amplify basal and antigen receptor-induced Src family kinase activation. Lyn expression was required for CD19 tyrosine phosphorylation in primary B cells. Experiments with purified proteins demonstrated that CD19-Y513 was Lyn's initial phosphorylation and binding site. This led to processive phosphorylation of CD19-Y482, which recruited a second Lyn molecule, allowing for transphosphorylation and amplification of Lyn activation. In vivo, CD19 deficiency impaired, and CD19 overexpression enhanced, Lyn kinase activity. Thus, CD19 functions as a specialized adapter protein for the amplification of Src family kinases that is crucial for intrinsic and antigen receptor-induced signal transduction.
Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.
M
M
Fujimoto
Y
Y
Fujimoto
J C
JC
Poe
P J
PJ
Jansen
C A
CA
Lowell
A L
AL
DeFranco
T F
TF
Tedder
D000595:Amino Acid Sequence; D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D001665:Binding Sites; D002417:Cattle; D018797:Cell Cycle Proteins; D004789:Enzyme Activation; D015870:Gene Expression; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav; D013379:Substrate Specificity; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D018941:Antigens, CD19; D018797:Cell Cycle Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; C496619:Vav1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases