Targets of B-cell antigen receptor signaling: the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 signaling pathway and the Rap1 GTPase

Gold, Michael R
Ingham, Robert J
McLeod, Sarah J
Christian, Sherri L
Scheid, Michael P
Duronio, Vincent
Santos, Lorna
Matsuuchi, Linda

Authors' addresses Michael R. Gold¹, Robert J. Ingham¹, Sarah J. McLeod¹, Sherri L. Christian¹, Michael P. Scheid², Vincent Duronio², Lorna Santos³, Linda Matsuuchi³, ¹Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada. ²Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. ³Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada.

Correspondence to: Michael R. Gold; Department of Microbiology and Immunology; University of British Columbia; 6174 University Blvd; Vancouver; British Columbia V6T 1Z3; Canada; Fax: 1 604 822 6041; e-mail: [email protected]

Acknowledgements Our research has been supported by grants from the Medical Research Council (MRC) of Canada, the Cancer Research Society (Canada), and the Natural Sciences and Engineering Research Council (NSERC) of Canada. We thank May Dang-Lawson for technical assistance and Drs Albert Wong, Tomohiro Kurosaki, Michael Ratcliffe, Michiyuki Matsuda, Johannes Bos, and Jeffrey DeClue for providing us with key reagents and cell lines. We thank Dr Steven Pelech for providing Fig. 4.

Immunological Reviews 176:p 47-68, August 2000.

Summary:

In this review, we discuss the role of phosphatidylinositol 3-kinase (PI3K) and Rap1 in B-cell receptor (BCR) signaling. PI3K produces lipids that recruit pleckstrin homology domain-containing proteins to the plasma membrane. Akt is a kinase that the BCR activates in this manner. Akt phosphorylates several transcription factors as well as proteins that regulate apoptosis and protein synthesis. Akt also regulates glycogen synthase kinase-3, a kinase whose substrates include the nuclear factor of activated T cells (NF-AT)c1 and β-catenin transcriptional activators. In addition to Akt, PI3K-derived lipids also regulate the activity and localization of other targets of BCR signaling. Thus, a key event in BCR signaling is the recruitment of PI3K to the plasma membrane where its substrates are located. This is mediated by binding of the Src homology (SH) 2 domains in PI3K to phosphotyrosine-containing sequences on membrane-associated docking proteins. The docking proteins that the BCR uses to recruit PI3K include CD19, Cbl, Gab1, and perhaps Gab2. We have shown that Gab1 colocalizes PI3K with SH2 domain-containing inositol phosphatase (SHIP) and SHP2, two enzymes that regulate PI3K-dependent signaling. In contrast to PI3K, little is known about the Rap1 GTPase. We showed that the BCR activates Rap1 via phospholipase C-dependent production of diacylglycerol. Since Rap1 is thought to regulate cell adhesion and cell polarity, it may be involved in B-cell migration.