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(Received for publication, May 17, 1996)
From the ABSTRACT CDC37 was originally identified as a
Start gene in budding yeast and has been shown to be required for
association of CDC28 with cyclins. The exact functional mechanism by
which CDC37 promotes this association, however, remains unknown. CDK4
is a cyclin D-dependent kinase that controls progression
through G1 of the mammalian cell cycle. We have detected a
specific association of CDK4 with the molecular chaperon HSP90 and a
44-kDa protein that we identify as mammalian CDC37. A physical
interaction between CDC37 and CDK4 suggests that CDC37 may regulate the
mammalian cell cycle through a direct effect on CDK4. Association of
CDK4 with both CDC37 and HSP90 may also imply a mechanistic link
between the functions of CDC37 and HSP90.
INTRODUCTION In mammalian cells, ordered activation of
cyclin-dependent kinases
(CDKs)1 governs the progression through
different phases of the cell cycle (1, 2, 3, 4). CDK4 is one of the CDKs that
control the G1-to-S phase transition. Activation of CDK4
requires binding to one of the D-type cyclins (D1, D2, or D3) (5) and
phosphorylation by the CDK-activating kinase (CAK) (6). As cells enter
the cycle from quiescence (G0) in response to growth
signals, CDK4 and cyclin D are synthesized and assemble into
CDK4-cyclin D complexes. The assembly of CDK4-cyclin D complexes may
also require an as yet unidentified upstream regulatory factor(s),
since complex assembly in cells with ectopically expressed CDK4 and
cyclin D is still dependent on mitogenic signals (7). Although required
for the activation of CDK4, phosphorylation by CAK appears not needed
for the assembly of CDK4-cyclin D complexes (6). Therefore, although
much has been known about the functional mechanism and regulation of
CDKs and their cyclin partners, new regulatory proteins and regulation
pathways remain to be uncovered.
In order to identify other proteins involved in CDK4 regulation, we
analyzed CDK4 complexes in various mammalian cells by an approach
employed in our previous studies (8, 9, 10, 11). We report the discovery of a
direct association of CDK4 with mammalian CDC37, a protein potentially
essential for activation of CDK4.
EXPERIMENTAL PROCEDURES S6, WMN, and ML-1 cells were
grown in RPMI 1640 containing 10% fetal bovine serum. NIH3T3 (ATCC CRL
1658) cells were grown in DMEM supplemented with 10% calf serum. The
S6 is a subclone of mouse myeloid cell line M1 (13). WMN, a human
Burkitt's lymphoma cell line, was kindly provided by Dr. Patrick M. O'Connor (National Cancer Institute, Bethesda, MD). Ml-1, a human
myeloid cell line, was obtained from cell culture facilities at Cold
Spring Harbor Laboratory (Cold Spring Harbor, NY). The antibody used to
immunoprecipitate CDK4 from mouse cells was purchased from Santa Cruz
Biotechnology, Inc., Santa Cruz, CA: catalog number sc-260). It was
raised against a peptide at the carboxyl terminus of CDK4 of mouse
origin. The antibody used to immunoprecipitate CDK4 from human cells
has been described (8). The anti-HSP90 monoclonal antibody was
purchased from StressGen Biotechnologies Corp. (catalog
number SPA-830, Victoria, British Columbia, Canada). It exhibits
cross-reactivity with HSP90 from human and mouse. In
immunoprecipitation, it strongly favors free HSP90 over complexed
HSP90. The anti-CDC37 antibody was raised against the GST-CDC37 (human)
fusion, and it cross-reacts with mouse CDC37 in immunoprecipitation
assay.
Metabolic labeling of cells with
[35S]methionine and immunoprecipitation of labeled
proteins were performed as described before (9). For glycerol gradient
sedimentation analysis, log-phase growing S6 cells were labeled with
[35S]methionine. The cells were lysed in 300 µl of
immunoprecipitation lysis buffer (50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 0.5% Nonidet P-40, 1 mM sodium
vanadate, 50 mM NaF, 5 µg/ml each of the following
protease inhibitors: aprotinin, leupeptin, soybean trypsin inhibitor,
and 1 mM benzamidine). The lysates were cleared of nuclear
fractions and loaded onto a 15-35% glycerol gradient prepared in the
lysis buffer. The gradient was centrifuged at 40,000 rpm in a SW41.Ti
rotor (Beckman) at 4 °C for 36 h. After centrifugation,
300-µl fractions were collected from the top of the gradient, diluted
in 700 µl of lysis buffer, and immunoprecipitated with anti-CDK4
antibody.
Human CDC37, CDKs, CAK, and cyclin D1 were in
vitro translated using the TNT-lysate in vitro
translation kit (Promaga) following manufacturer's instructions.
In vitro protein binding assay was carried out essentially
as described previously (12). Briefly, GST-CDC37 or GST (negative
control) (1 µg) was incubated with the in vitro translated
CDK or cyclin D1 for 30 min at 30 °C in 50 µl containing 20 mM Tris-HCl, pH 8.0, 10 mM MgCl2, 1 mM EGTA. After incubation, 200 µl of lysis buffer and 15 µl of glutathione-Sepharose were added to the mixture, and the
incubation was continued for 1 h. Beads were washed four times
with 1 ml of IP buffer before heated for SDS-PAGE analysis. Partial
Staphylococcus aureus V8 protease mapping of CDC37 and HSP90
was performed as described before (8, 14).
RESULTS -To uncover novel CDK4
regulatory protein(s), we analyzed CDK4 complexes in various cells by
immunoprecipitation using anti-CDK4 antibodies. In S6 cells, a mouse
myeloid cell line (13), two proteins, one with a molecular mass of 44 kDa, the other 85 kDa, were found to co-immunoprecipitate with CDK4
(Fig. 1a). Similar proteins were also found
in CDK4 immunoprecipitates from several other mouse and human cells
(Fig. 1a and not shown). No proteins with similar molecular
masses have been reported previously to associate with CDK4, and the
two proteins were therefore further characterized. To confirm the
association of the two proteins with CDK4, extracts of S6 cells were
separated by glycerol gradient centrifugation, and the fractions were
immunoprecipitated with anti-CDK4 antibodies. Both p44 and p85 were
found to co-sediment with CDK4 (Fig. 1b). The levels of CDK4
and p44 peaked both in fraction 12 and the heavier fraction 22. Fraction 12 also displays a peak of cyclin D1, whereas the cyclin is
absent from the heavier fraction (22), which instead contains p85.
Co-sedimentation of CDK4, p44, and p85, however, may suggest that they
form a ternary complex.
Previously, we purified an 85-kDa protein as a CDK6-associated protein
and identified it as HSP90 by peptide
sequencing.2 To determine whether the
CDK4-associated p85 is the same protein, an anti-HSP90 monoclonal
antibody was used to immunoprecipitate HSP90 from mouse or human cells.
The immunoprecipitated HSP90 co-migrated with p85 (Fig. 1a).
V8 proteolytic digest patterns of HSP90 and p85 from both mouse and
human cells were essentially identical (Fig. 1c). Based on
these results, we conclude that the CDK4-associated p85 is HSP90.
In order to
identify p44, the protein was purified from S6 cells using an anti-CDK4
affinity column essentially as described previously (11). S6 was chosen
mainly because of the abundance of p44 in the CDK4 immunoprecipitates
from these cells. Peptide sequence analysis was carried out on four p44
fragments generated by Achromobacter lyticus protease I
digestion. Sequences for three of these were either identical or highly
related to sequences contained in the chicken and Drosophila
homologues of CDC37 (15, 16) (Fig. 2b). Four
human cDNA clones in the dbEST data base that encode a peptide with
homology to known CDC37 proteins were found. Clone R87892 (GenBankTM
ID) that contains the longest cDNA insert (1.7 kilobase pairs) was
obtained from Genome System Inc., and its nucleotide sequence was
determined. An open reading frame of 378 amino acids was found (Fig.
2a). The putative polypeptide has a predicted molecular mass
of 44.5 kDa, and the amino acid sequence has a nearly perfect match
with the four mouse p44-derived peptide sequences (Fig. 2b).
A search of the existing data bases did not reveal significant homology
to known polypeptides other than CDC37. The protein shares 45% amino
acid identity with D. melanogaster CDC37 (16) and 25% amino
acid identity with S. cerevisiae CDC37 (17, 18), while the
latter two share amino acid identity of 27%. The most conserved region
of the CDC37 proteins of different species is at the NH2
terminus, indicating a possible critical role of this region in the
function of CDC37 proteins. Based on the sequence similarity, we
conclude that this cDNA encodes the human CDC37 protein.
Several experiments confirmed that CDC37 and the CDK4-associated p44
are the same proteins. The cDNA for human CDC37 was translated
in vitro and the translation product co-migrated with p44
from human cells in SDS-PAGE gels (Fig. 3a, left
panel). In addition, the V8 protease digestion patterns of the two
proteins were almost indistinguishable (Fig. 3a, right
panel, note particularly the 500 ng lanes). Furthermore, an
anti-CDC37 serum was used to immunoprecipitate mouse CDC37 from S6
cells (Fig. 3b). Comparison of the mouse CDC37 with mouse
p44 following V8 protease digestion and electrophoresis also
demonstrates that they are the same proteins. Finally, the association
of CDC37 with CDK4 was tested in vitro using a GST-CDC37
fusion expressed and purified from Escherichia coli. The
human CDC37 fusion protein specifically bound to CDK4 translated
in vitro (Fig. 3a, lower panel).
DISCUSSION We have demonstrated a physical interaction between mammalian
CDC37 and CDK4 in both mouse and human cells. We have also shown
evidence for an association of CDK4 with HSP90. The CDC37
gene was first identified in S. cerevisiae by mutations that
cause cell cycle arrest in G1 (17). Recently, it has been shown that
the yeast CDC37 protein is required for the association of CDC28 with
cyclins and that a defect in CDC37 prevents CDC28 activation (19). A
similar role might be expected for mammalian CDC37 in the activation of
CDK4. Previously, a CAK-associated protein (MAT1) was cloned and shown
to facilitate the assembly of the CAK-cyclin H complex (20, 21). If
mammalian CDC37 would similarly stimulate CDK4-cyclin D complex
assembly remains to be determined. It seems likely, however, that
``facilitator'' proteins might be a general requirement for the
generation of active CDK-cyclin complexes in mammalian cells. Playing a
possibly essential role in the activation of their associating CDKs,
these proteins could be potential regulation points.
HSP90 functions as a molecular chaperone (22, 23). It is associated
with and required for the activity of a number of kinases and steroid
receptors (22, 24, 25, 26, 27). Increasing evidence suggests that CDC37 may
functionally interact with HSP90. In S. cerevisiae, either
mutations in CDC37 or a reduction in the level of the yeast
HSP90 protein were found to suppress the lethality of overexpression of
v-Src (28, 29). In D. melanogaster, mutations in
CDC37 and hsp90 have been isolated in a screen for mutations
that exacerbate a defect in the sevenless receptor tyrosine kinase
(16). Our finding, in mammalian cells, that CDC37 and HSP90 are both
associated with CDK4 and that the three proteins may possibly form a
ternary complex could suggest a direct mechanistic link between CDC37
and HSP90. It is possible that CDK37 and HSP90 act in concert to
facilitate the proper folding of CDK4 for complex assembly with D-type
cyclins. Partner proteins that presumably function in concert with
HSP90 have been found in a number of HSP90 complexes with its target
proteins, including steroid hormone receptors, Raf and v-Src kinases
(22, 27, 30. 31). The exact role and functional mechanism of these
proteins are yet to be elucidated. Some studies suggest that
association with HSP90 and the partner proteins is important for the
stabilization and intracellular trafficking of the target protein (30,
31). Whether CDC37 and HSP90 have a similar effect on CDK4 stability
and transport is currently under investigation.
FOOTNOTES Acknowledgments We thank D. Conklin, G. J. Hannon, K. Galaktionov for critical reading of the manuscript and valuable
suggestions, and thank M. Serrano, H. Zhang (Yale University), and K. Okamoto (Columbia University) for helpful discussion. We also thank J. Duffy, P. Renna, M. Ockler for the artwork. The anti-CDK4 cross-linked
Sepharose is a gift from Santa Cruz Biotechnology, Inc.
REFERENCES
Volume 271, Number 36,
Issue of September 6, 1996
pp. 22030-22034
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
§,
Howard Hughes Medical Institute, ¶ Cold
Spring Harbor Laboratory, Cold Spring Harbor, New York 11724
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
FOOTNOTES
Acknowledgments
REFERENCES
Fig. 1.
Association of CDK4 with HSP90 and p44.
a, analysis of CDK4-associated proteins by
immunoprecipitation. [35S]Methionine-labeled lysates of
mouse (S6, NIH3T3) and human (WMN, ML-1) cells
were immunoprecipitated with anti-CDK4 antibody with (+) or without
(
) preincubation with the antigen peptide. The immunoprecipitates
were analyzed by 15% SDS-PAGE. The HSP90 proteins in mouse and human
cells were immunoprecipitated with an anti-HSP90 antibody and run in
the same gel for comparison with CDK4-associated p85. Positions of the
molecular mass markers (kDa), CDK4, p85/HSP90, and p44, are marked.
b, analysis of CDK4 complexes by glycerol gradient
sedimentation. [35S]Methionine-labeled S6 cell lysate was
sedimented in 15-35% glycerol gradient. Proteins in every second
fraction were immunoprecipitated with anti-CDK4 antibody and the
immunoprecipitates were separated by 15% SDS-PAGE. Immunoprecipitates
from the starting total lysate were shown on the left. Positions of
CDK4-cyclin D1 (CYCD1), p85/HSP90, and p44/CDC37 are marked.
c, comparison of p85 with HSP90 by V8 protease mapping.
Immunoprecipitates by antibodies to CDK4 or HSP90 were first separated
by 15% SDS-PAGE. Protein bands corresponding to p85 and HSP90 (Fig.
1a) were excised and digested with V8 protease, and the
digests were analyzed by 17.5% SDS-PAGE.
Fig. 2.
Sequences of CDC37. a, the
nucleotide sequence of the human CDC37 cDNA along with the deduced
amino acid sequence of the human CDC37 protein. b, the
deduced amino acid sequence of the human CDC37 protein
(Human) is compared with those of the D. melanogaster (Drosophila) and S. cerevisiae
(Yeast) CDC37 proteins. Four peptide sequences obtained from
the purified mouse CDC37 is also shown at the top (boxed).
Areas of homology was identified using DNA Star MegAlign program. The
shaded regions indicate identity.
Fig. 3.
Identification of p44 as mammalian CDC37.
a, human CDC37 was in vitro translated and
compared with the CDK4-associated p44 from WMN cells by electrophoresis
in 15% SDS-PAGE (left panel) and by V8 protease mapping
(right panel). Lower panel, human CDC37
specifically binds to CDK4. A fusion protein consisting of glutathione
S-transferase and human CDC37 (GST-hCDC37) was expressed and
purified from E. coli and mixed with equal amounts of
in vitro translated, 35S-labeled CDC2, CDK2,
CDK3, CDK4, CDK5, CDK6, CAK, or cyclin D1. Bound proteins were
recovered on glutathione-Sepharose and analyzed by 12.5% SDS-PAGE. GST
was used as negative control, and it had no binding to any of the above
proteins (data not shown). b, mouse CDC37 was
immunoprecipitated from S6 cells using an anti-CDC37 antibody
(left panel) and compared with mouse p44 from the same cells
by V8 protease mapping (right panel).
§
Supported by a National Institutes of Health postdoctoral
fellowship.
Investigator of the Howard Hughes Medical Institute. To whom
correspondence should be addressed: Cold Spring Harbor Laboratory, 1 Bungtown Rd., Cold Spring Harbor, NY 11724. Tel.: 516-367-8847; Fax:
516-367-8874.
1
The abbreviations used are: CDK,
cyclin-dependent kinase; CAK, CDK-activating kinase; PAGE,
polyacrylamide gel electrophoresis; GST, glutathione
S-transferase.
2
K. Dai, R. Kobayashi, and D. Beach, unpublished
results.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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J. Shao, N. Grammatikakis, B. T. Scroggins, S. Uma, W. Huang, J.-J. Chen, S. D. Hartson, and R. L. Matts Hsp90 Regulates p50cdc37 Function during the Biogenesis of the Active Conformation of the Heme-regulated eIF2alpha Kinase J. Biol. Chem., January 5, 2001; 276(1): 206 - 214. [Abstract] [Full Text] [PDF]
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Y. Miyata, Y. Ikawa, M. Shibuya, and E. Nishida Specific Association of a Set of Molecular Chaperones Including HSP90 and Cdc37 with MOK, a Member of the Mitogen-activated Protein Kinase Superfamily J. Biol. Chem., June 8, 2001; 276(24): 21841 - 21848. [Abstract] [Full Text] [PDF]
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