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J. Biol. Chem., Vol. 269, Issue 50, 31552-31562, Dec, 1994
JH Stack and SD Emr
The Vps15 protein kinase and the Vps34 phosphatidylinositol 3-kinase have
been shown to function as a membrane-associated complex which facilitates
the delivery of proteins to the vacuole in yeast. Biochemical
characterization of the autophosphorylation reaction catalyzed by Vps15p
demonstrates that it is a functional serine/threonine protein kinase. In
addition, we show that the Vps34 phosphatidylinositol 3-kinase undergoes an
autophosphorylation event both in vivo and in vitro, indicating that it
represents a novel multiple specificity kinase capable of phosphorylating
both protein and lipid substrates. Vps34p is phosphorylated predominately
on serine in vivo and is able to phosphorylate serine, threonine, and
tyrosine residues in vitro. Mutant Vps34 proteins containing alterations in
conserved amino acids in the lipid kinase domain are severely defective for
both PI 3-kinase activity and autophosphorylation. Characterization of the
PI 3-kinase activity of Vps34p demonstrates that it, unlike the mammalian
p110 PI 3-kinase, is highly resistant to the PI 3-kinase inhibitors
wortmannin and LY294002. We also find that Vps34p is a
phosphatidylinositol-specific 3-kinase, as it is able to utilize
phosphatidylinositol (PtdIns) but not PtdIns(4)P or PtdIns(4,5)P2 as
substrates in an in vitro PI kinase reaction. The substrate specificity,
wortmannin resistance, and other biochemical characteristics of its PtdIns
3-kinase activity suggest that Vps34p is quite similar to a PtdIns-specific
3-kinase activity recently characterized from mammalian cells. These data
indicate the existence of a family of PI 3-kinases composed of p110-like PI
3-kinases and Vps34p-like PtdIns-specific 3-kinases. On the basis of the
role for Vps34p in vacuolar protein sorting, we propose that the production
of a specific phosphoinositide, PtdIns(3)P, is involved in regulating
intracellular protein sorting reactions in eukaryotic cells.
Vps34p required for yeast vacuolar protein sorting is a multiple specificity kinase that exhibits both protein kinase and phosphatidylinositol-specific PI 3-kinase activities
Division of Cellular and Molecular Medicine, Howard Hughes Medical Institute, University of California, San Diego School of Medicine, La Jolla 92093-0668.
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