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Vol. 13, Issue 9, 3005-3028, September 2002
and
Department of Molecular and Cell Biology, Division of Biochemistry
and Molecular Biology, University of California, Berkeley, California
94720-3202
Saccharomyces cerevisiae Pkh1 and Pkh2 are
functionally redundant homologs of mammalian protein kinase,
phosphoinositide-dependent protein kinase-1. They activate two
closely related, functionally redundant enzymes, Ypk1 and Ykr2
(homologs of mammalian protein kinase, serum- and
glucocorticoid-inducible protein kinase). We found that Ypk1 has a more
prominent role than Ykr2 in mediating their shared essential function.
Considerable evidence demonstrated that Pkh1 preferentially activates
Ypk1, whereas Pkh2 preferentially activates Ykr2. Loss of Pkh1 (but not
Pkh2) reduced Ypk1 activity; conversely, Pkh1 overexpression increased
Ypk1 activity more than Pkh2 overexpression. Loss of Pkh2 reduced Ykr2
activity; correspondingly, Pkh2 overexpression increased Ykr2 activity
more than Pkh1 overexpression. When overexpressed, a catalytically
active C-terminal fragment (kinase domain) of Ypk1 was growth
inhibitory; loss of Pkh1 (but not Pkh2) alleviated toxicity. Loss of
Pkh2 (but not Pkh1) exacerbated the slow growth phenotype of a
ypk1
strain. This Pkh1-Ypk1 and Pkh2-Ykr2 dichotomy
is not absolute because all double mutants (pkh1
ypk1, pkh2 ypk1, pkh1
ykr2, and pkh2 ykr2) were viable.
Compartmentation contributes to selectivity because Pkh1 and Ypk1 were
located exclusively in the cytosol, whereas Pkh2 and Ykr2 entered the
nucleus. At restrictive temperature,
ypk1-1ts ykr2 cells
lysed rapidly, but not in medium containing osmotic support. Dosage and
extragenic suppressors were selected. Overexpression of Exg1 (major
exoglucanase), or loss of Kex2 (endoprotease involved in Exg1
processing), rescued growth at high temperature. Viability was also
maintained by PKC1 overexpression or an activated allele of the downstream protein kinase (BCK1-20). Conversely,
absence of Mpk1 (distal mitogen-activated protein kinase of the
PKC1 pathway) was lethal in
ypk1-1ts ykr2 cells.
Thus, Pkh1-Ypk1 and Pkh2-Ykr2 function in a novel pathway for cell wall
integrity that acts in parallel with the Pkc1-dependent pathway.
GeneLabs Technologies, Inc., Redwood
City, CA 94603;
Sangamo Biosciences, Inc., Richmond, CA 94804.
§
Corresponding author. E-mail address:
jeremy{at}socrates.berkeley.edu.
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