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J. Biol. Chem., Vol. 277, Issue 25, 22115-22118, June 21, 2002
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,,
From the Department of Biochemistry, Dartmouth Medical School,
Hanover, New Hampshire 03755 and the § Harvard
Microchemistry and Proteomics Analysis Facility, Department of
Molecular and Cellular Biology, Harvard University,
Cambridge, Massachusetts 02138
This study describes a method for the
identification of the substrates of specific serine kinases. An
antibody specific for the phosphomotif generated by the kinase is used
to isolate phosphorylated substrates by immunoprecipitation, and the
isolated proteins are identified by tandem mass spectrometry of
peptides. This method was applied to the identification of substrates
for the protein kinase Akt, which specifically
phosphorylates the RXRXXS/T motif. 3T3-L1 adipocytes were treated with insulin to activate Akt, and the
putative Akt substrate proteins were isolated by immunoprecipitation with an antibody against the phospho form of this motif. This led to
the identification of a novel 160-kDa substrate for Akt. The 160-kDa
substrate for Akt, which was designated AS160, has a Rab GAP domain.
Recombinant AS160 was shown to be a substrate for Akt, and two sites of
phosphorylation, both in RXRXXS/T motifs, were
identified by mass spectrometry and mutation. Insulin treatment of
adipocytes caused AS160 to redistribute from the low density microsomes
to the cytosol.
These authors contributed equally to this study.
¶
Permanent address: Dept. of Chemistry, Abilene Christian
University, Abilene, TX 79699.
To whom correspondence should be addressed: Dept. of
Biochemistry, Vail Bldg., Dartmouth Medical School, Hanover, NH 03755. Tel.: 603-650-1627; Fax: 603-650-1128; E-mail:
gustav.e.lienhard@dartmouth.edu.
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