The generation of phosphatidylinositide 3-phosphates has been observed in a variety of cellular responses. The enzymes that mediate synthesis are the phosphoinositide 3-kinases (PI3-Ks) that form a family of structurally diverse enzymes with distinct substrate specificities. In this paper, we describe the cloning of a novel human PI3-K, namely PI3-K-C2α, which contains a C-terminal C2 domain. This enzyme can be assigned to the class II PI3-Ks, which was defined by characterization of the Drosophila 68D enzyme and includes the recently described murine enzymes m-cpk and p170. Despite the overall similarity in the amino acid sequence of the murine and human enzymes, which suggests that they are encoded by closely related genes, these molecules show marked sequence heterogeneity at their N-termini. Biochemical analysis of recombinant PI3-K-C2α demonstrates a restricted lipid substrate specificity. As reported for other members of this class, the enzyme only phosphorylates PtdIns and PtdIns4P when the lipids are presented alone. However, when lipids were presented together with phosphatidylserine acting as a carrier, phosphorylation of PtdIns(4,5)P2 was also observed. The catalytic activity of PI3-K-C2α is refractory to concentrations of wortmannin and LY294002 which inhibit the PI3-K activity of other family members. The comparative insensitivity of PI3-K-C2α to these inhibitors suggests that their use should be re-evaluated in the study of PI3-Ks.
Skip Nav Destination
Article navigation
August 1997
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
Research Article|
August 15 1997
Cloning of a human phosphoinositide 3-kinase with a C2 domain that displays reduced sensitivity to the inhibitor wortmannin
Jan DOMIN;
Jan DOMIN
1
*Ludwig Institute for Cancer Research, London W1P 8BT, U.K.
Search for other works by this author on:
Françoise PAGES;
Françoise PAGES
1
*Ludwig Institute for Cancer Research, London W1P 8BT, U.K.
Search for other works by this author on:
Stefano VOLINIA;
Stefano VOLINIA
†Dipartimento di Biochemica e Biologia Molecolare, Università degli Studi, Via Borsari 46, 44100 Ferrara, Italy
Search for other works by this author on:
Susan E. RITTENHOUSE;
Susan E. RITTENHOUSE
‡Kimmel Cancer Institute/Jefferson Medical College, Philadelphia, PA 19107, U.S.A.
Search for other works by this author on:
Marketa J. ZVELEBIL;
Marketa J. ZVELEBIL
*Ludwig Institute for Cancer Research, London W1P 8BT, U.K.
Search for other works by this author on:
Rob C. STEIN;
Rob C. STEIN
*Ludwig Institute for Cancer Research, London W1P 8BT, U.K.
Search for other works by this author on:
Michael D. WATERFIELD
Michael D. WATERFIELD
2
*Ludwig Institute for Cancer Research, London W1P 8BT, U.K.
§Department of Biochemistry and Molecular Biology, University College, London WC1E 6BT, U.K.
2To whom correspondence should be addressed.
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
December 13 1996
Revision Received:
April 02 1997
Accepted:
April 15 1997
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1997
1997
Biochem J (1997) 326 (1): 139–147.
Article history
Received:
December 13 1996
Revision Received:
April 02 1997
Accepted:
April 15 1997
Citation
Jan DOMIN, Françoise PAGES, Stefano VOLINIA, Susan E. RITTENHOUSE, Marketa J. ZVELEBIL, Rob C. STEIN, Michael D. WATERFIELD; Cloning of a human phosphoinositide 3-kinase with a C2 domain that displays reduced sensitivity to the inhibitor wortmannin. Biochem J 15 August 1997; 326 (1): 139–147. doi: https://doi.org/10.1042/bj3260139
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.