Vav3 modulates B cell receptor responses by regulating phosphoinositide 3-kinase activation.
To elucidate the mechanism(s) by which Vav3, a new member of the Vav family proteins, participates in B cell antigen receptor (BCR) signaling, we have generated a B cell line deficient in Vav3. Here we report that Vav3 influences phosphoinositide 3-kinase (PI3K) function through Rac1 in that phosphatidylinositol-3,4,5-trisphosphate (PIP3) generation was attenuated by loss of Vav3 or by expression of a dominant negative form of Rac1. The functional interaction between PI3K and Rac1 was also demonstrated by increased PI3K activity in the presence of GTP-bound Rac1. In addition, we show that defects of calcium mobilization and c-Jun NH2-terminal kinase (JNK) activation in Vav3-deficient cells are relieved by deletion of a PIP3 hydrolyzing enzyme, SH2 domain-containing inositol polyphosphate 5'-phosphatase (SHIP). Hence, our results suggest a role for Vav3 in regulating the B cell responses by promoting the sustained production of PIP3 and thereby calcium flux.
Inabe
Kazunori
K
Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi 570-8506, Japan.
Ishiai
Masamichi
M
Scharenberg
Andrew M
AM
Freshney
Norman
N
Downward
Julian
J
Kurosaki
Tomohiro
T
D000818:Animals; D002118:Calcium / Q000276:immunology; D018797:Cell Cycle Proteins; D002460:Cell Line; D002645:Chickens; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D051567:Proto-Oncogene Proteins c-vav; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000276:immunology
D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011947:Receptors, Antigen, B-Cell; C496621:VAV3 protein, human; D019869:Phosphatidylinositol 3-Kinases; D020830:rac1 GTP-Binding Protein; D002118:Calcium