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J. Biol. Chem., Vol. 275, Issue 46, 36108-36115, November 17, 2000
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§¶
**,§§§,§,§,§¶¶
From the Departments of AKT was originally identified as a proto-oncogene
with a pleckstrin homology and Ser/Thr protein kinase domains.
Recent studies revealed that AKT regulates a variety of cellular
functions including cell survival, cell growth, cell differentiation,
cell cycle progression, transcription, translation, and cellular
metabolism. To clarify the substrate specificity of AKT, we have used
an oriented peptide library approach to determine optimal amino acids
at positions N-terminal and C-terminal to the site of phosphorylation.
The predicted optimal peptide substrate
(Arg-Lys-Arg-Xaa-Arg-Thr-Tyr-Ser*-Phe-Gly where Ser* is the
phosphorylation site) has similarities to but is distinct from optimal
substrates that we previously defined for related basophilic protein
kinases such as protein kinase A, Ser/Arg-rich kinases, and protein
kinase C family members. The positions most important for high
Vmax/Km ratio were Arg-3>Arg-5>Arg-7. The substrate specificity of AKT was further investigated by screening a Medicine and
Surgery, Beth Israel Deaconess Medical
Center and the § Department of Cell Biology, Harvard
Medical School, Boston, Massachusetts 02215 and the ¶ Third
Department of Medicine, Shiga University of Medical Science, Otsu,
Shiga 520-2192, Japan
GEX phage HeLa cell cDNA expression library. All of the substrates identified by this procedure contained Arg-Xaa-Arg-Xaa-Xaa-(Ser/Thr) motifs and were in close agreement with
the motif identified by peptide library screening. The results of this
study should help in prediction of likely AKT substrates from
primary sequences.
These authors contributed equally to this work.
**
Supported by the Kanae Foundation and the Uehara Memorial Foundation.
§§
Supported by National Institutes of Health Grant HL03601 and the
recipient of a Burroughs-Wellcome Career Development Award.
¶¶
To whom correspondence should be addressed: Division of
Signal Transduction, Harvard Institutes of Medicine, 10th Floor, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-0947; Fax:
617-667-0957; E-mail: cantley@helix.mgh.harvard.edu.
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