TY - JOUR
T1 - The inositol phosphatase SHIP inhibits Akt/PKB activation in B cells
AU - Aman, M. Javad
AU - Lamkin, Thomas D.
AU - Okada, Hidetaka
AU - Kurosaki, Tomohiro
AU - Ravichandran, Kodimangalam S.
PY - 1998/12/18
Y1 - 1998/12/18
N2 - The serine-threonine kinase Akt/PKB is activated downstream of phosphatidylinositol 3-kinase in response to several growth factor stimuli and has been implicated in the promotion of cell survival. Although both phosphatidylinositol 3,4,5-trisphosphate (PIP3) and phosphatidylinositol 3,4-bisphosphate (PI 3,4-P2) have been implicated in the regulation of Akt activity in vitro, the relative roles of these two phospholipids in vivo are not well understood. Co-ligation of the B cell receptor (BCR) and the inhibitory F(c)γRIIB1 on B cells results in the recruitment of the 5'- inositol phosphatase SHIP to the signaling complex. Since SHIP is known to cleave PIP3 to generate PI 3,4-P2 both in vivo and in vitro, and Akt activity has been reported to be regulated by either PIP3 or PI 3,4-P3, we hypothesized that recruitment of SHIP through F(c)γRIIB1 co-cross-linking to the BCR in B cells might regulate Akt activity. The nature of this regulation, positive or negative, might also reveal the relative contribution of PIP3 and PI 3,4-P2 to Akt activation in vivo. Here we report that Akt is activated by stimulation through the BCR in a phosphatidylinositol 3-kinase- dependent manner and that this activation is inhibited by co-cross-linking of the BCR to F(c)γRIIB1. Using mutants of F(c)γRIIB1 and SHIP-deficient B cells, we demonstrate that inhibition of Akt activity is mediated by the immune cell tyrosine-based inhibitory motif within F(c)γRIIB1 as well as SHIP. The SHIP-dependent inhibition of Akt activation also suggests that PIP3 plays a greater role in Akt activation than PI 3,4-P2 in vivo.
AB - The serine-threonine kinase Akt/PKB is activated downstream of phosphatidylinositol 3-kinase in response to several growth factor stimuli and has been implicated in the promotion of cell survival. Although both phosphatidylinositol 3,4,5-trisphosphate (PIP3) and phosphatidylinositol 3,4-bisphosphate (PI 3,4-P2) have been implicated in the regulation of Akt activity in vitro, the relative roles of these two phospholipids in vivo are not well understood. Co-ligation of the B cell receptor (BCR) and the inhibitory F(c)γRIIB1 on B cells results in the recruitment of the 5'- inositol phosphatase SHIP to the signaling complex. Since SHIP is known to cleave PIP3 to generate PI 3,4-P2 both in vivo and in vitro, and Akt activity has been reported to be regulated by either PIP3 or PI 3,4-P3, we hypothesized that recruitment of SHIP through F(c)γRIIB1 co-cross-linking to the BCR in B cells might regulate Akt activity. The nature of this regulation, positive or negative, might also reveal the relative contribution of PIP3 and PI 3,4-P2 to Akt activation in vivo. Here we report that Akt is activated by stimulation through the BCR in a phosphatidylinositol 3-kinase- dependent manner and that this activation is inhibited by co-cross-linking of the BCR to F(c)γRIIB1. Using mutants of F(c)γRIIB1 and SHIP-deficient B cells, we demonstrate that inhibition of Akt activity is mediated by the immune cell tyrosine-based inhibitory motif within F(c)γRIIB1 as well as SHIP. The SHIP-dependent inhibition of Akt activation also suggests that PIP3 plays a greater role in Akt activation than PI 3,4-P2 in vivo.
UR - http://www.scopus.com/inward/record.url?scp=0032545343&partnerID=8YFLogxK
U2 - 10.1074/jbc.273.51.33922
DO - 10.1074/jbc.273.51.33922
M3 - Article
C2 - 9852043
AN - SCOPUS:0032545343
VL - 273
SP - 33922
EP - 33928
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 51
ER -