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J. Biol. Chem. 277 (2): 912-921

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Phosphatidylinositol 3-Kinase p85 Adaptor Function in T-cells
CO-STIMULATION AND REGULATION OF CYTOKINE TRANSCRIPTION INDEPENDENT OF ASSOCIATED p110*

Hyun KangDagger §, Helga SchneiderDagger §, and Christopher E. RuddDagger ||**

From the Dagger  Department of Cancer Immunology and AIDS, the § Dana-Farber Cancer Institute and Departments of Medicine and || Pathology, Harvard Medical School, Boston, Massachusetts 02115, and the  Department of Haematology, Hammersmith Hospital, Imperial College School of Medicine, Du Cane Road, London, W12 0NN United Kingdom

Phosphatidylinositol 3-kinase (PI3K) is a key regulator of a variety of cellular functions from cytoskeletal organization, vesicular trafficking, and cell proliferation to apoptosis. The enzyme complex is comprised of an 85-kDa adaptor (p85) coupled to a 110-kDa catalytic subunit (p110). While the function of PI3K has been largely attributed to the generation of D-3 lipids, an unanswered question has been whether p85 with a number of motifs (SH2, SH3, BcR homology (BH) region) can generate independent intracellular signals. In this study, we demonstrate that p85 lacking p110 (Delta p85) can activate NFAT transcription in T-cell hybridomas and normal splenocytes. This up-regulatory effect was unaffected by inhibition of PI 3-kinase, and cooperated specifically with Rac1, but not related family members. Stimulation correlated with Rac1 binding and was lost with the deletion of the BH domain. Lastly, the CD28-Delta p85 chimera also cooperated with TcR/CD3 to provide co-signals that enhanced IL-2 transcription. Our findings identify for the first time p85 as an adaptor that operates independently of the classic PI 3-kinase catalytic pathway and further shows that this pathway can provide co-signals in the regulation of T-cell function.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed. Tel.: 44 2083 838 421; Fax: 44 2083 838 434; E-mail: c.rudd@ic.ac.uk.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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