The chaperones Hsp90 and Cdc37 mediate the maturation and stabilization of protein kinase C through a conserved PXXP motif in the C-terminal tail.
Open accessAbstract
The life cycle of protein kinase C (PKC) is tightly controlled by mechanisms that mature the enzyme, sustain the activation-competent enzyme, and degrade the enzyme. Here we show that a conserved PXXP motif (Kannan, N., Haste, N., Taylor, S. S., and Neuwald, A. F. (2007) Proc. Natl. Acad. Sci. U. S. A. 104, 1272-1277), in the C-terminal tail of AGC (c-AMP-dependent protein kinase/protein kinase G/protein kinase C) kinases, controls the processing phosphorylation of conventional and novel PKC isozymes, a required step in the maturation of the enzyme into a signaling-competent species. Mutation of both Pro-616 and Pro-619 to Ala in the conventional PKC betaII abolishes the phosphorylation and activity of the kinase. Co-immunoprecipitation studies reveal that conventional and novel, but not atypical, PKC isozymes bind the chaperones Hsp90 and Cdc37 through a PXXP-dependent mechanism. Inhibitors of Hsp90 and Cdc37 significantly reduce the rate of processing phosphorylation of PKC. Of the two C-terminal sites processed by phosphorylation, the hydrophobic motif, but not the turn motif, is regulated by Hsp90. Overlay of purified Hsp90 onto a peptide array containing peptides covering the catalytic domain of PKC betaII identified regions surrounding the PXXP segment, but not the PXXP motif itself, as major binding determinants for Hsp90. These Hsp90-binding regions, however, are tethered to the C-terminal tail via a "molecular clamp" formed between the PXXP motif and a conserved Tyr (Tyr-446) in the alphaE-helix. Disruption of the clamp by mutation of the Tyr to Ala recapitulates the phosphorylation defect of mutating the PXXP motif. These data are consistent with a model in which a molecular clamp created by the PXXP motif in the C-terminal tail and determinants in the alphaE-helix of the catalytic domain allows the chaperones Hsp90 and Cdc37 to bind newly synthesized PKC, a required event in the processing of PKC by phosphorylation.
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In S. cerevisiae, Hsp90 may interact with PKC signaling by chaperoning PKC and the MAPK Slt2.
“In S. cerevisiae, Hsp90 may also interact with PKC signaling by chaperoning PKC [48] and the MAPK Slt2 [49],[50].”
From Hsp90 Governs Echinocandin Resistance in the Pathogenic Yeast Candida albicans via Calcineurin (2009) · cites this paper as [48]
The Discussion identifies PKC as an Hsp90–Cdc37 client whose maturation and stability depend on the chaperone. The Results describe PKC experiments in COS7 cells, not S. cerevisiae, so this source does not establish the yeast-specific part of the claim. The separate Slt2 claim is attributed to citations [49] and [50], not this paper. Page numbers were not provided in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn mammalian cells, Hsp90 physically interacts with the PKC isoenzyme ßII.
“In mammalian cells, Hsp90 physically interacts with the PKC isoenzyme ßII”
From Functional Genomic Screening Reveals Core Modulators of Echinocandin Stress Responses in Candida albicans (2018) · cites this paper as Gould et al., 2009
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Cites
The protein kinase complement of the human genome
Manning, G., Whyte, D. B., Martinez, R., Hunter, T., & Sudarsanam, S. (2002) · Science · doi:10.1126/science.1075762 · Cited by 8,145 · see citing works
Comprehensive genomic characterization defines human glioblastoma genes and core pathways
The Cancer Genome Atlas Research Network (2008) · Nature · doi:10.1038/nature07385 · Cited by 7,735 · see citing works
Molecular Chaperones in the Cytosol: from Nascent Chain to Folded Protein
Hartl, F. U., & Hayer-Hartl, M. K. (2002) · Science · doi:10.1126/science.1068408 · Cited by 3,335 · see citing works
Patterns of somatic mutation in human cancer genomes
Greenman, C. D., Stephens, P., Smith, R., Dalgliesh, G. L., Hunter, C., Bignell, G. R., Davies, H. R., Teague, J. W., Butler, A. P., Stevens, C., et al. (2007) · Nature · doi:10.1038/nature05610 · Cited by 3,062 · see citing works
HSP90 and the chaperoning of cancer
Whitesell, L., & Lindquist, S. L. (2005) · Nature Reviews Cancer · doi:10.1038/nrc1716 · Cited by 2,502 · see citing works
A monomeric red fluorescent protein
Campbell, R. E., Tour, O., Palmer, A. E., Steinbach, P. A., Baird, G. S., Zacharias, D. A., & Tsien, R. Y. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.082243699 · Cited by 2,346 · see citing works
The Conformational Plasticity of Protein Kinases
Huse, M., & Kuriyan, J. (2002) · Cell · doi:10.1016/s0092-8674(02)00741-9 · Cited by 1,760 · see citing works
Structure and mechanism of the Hsp90 molecular chaperone machinery
Pearl, L. H., & Prodromou, C. (2006) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.75.103004.142738 · Cited by 1,103 · see citing works
Modulation of Akt kinase activity by binding to Hsp90
Sato, S., Fujita, N., & Tsuruo, T. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.170276797 · Cited by 967 · see citing works
Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm
Newton, A. C. (2003) · Biochemical Journal · doi:10.1042/bj20021626 · Cited by 799 · see citing works
Self-citationBasso, A. D., Solit, D. B., Chiosis, G., Giri, B., Tsichlis, P., & Rosen, N. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206322200 · Cited by 628 · see citing works
Regulation of protein kinase C ζ by PI 3-kinase and PDK-1
Chou, M. M., Hou, W., Johnson, J. E., Graham, L. K., Lee, M. H., Chen, C., Newton, A. C., Schaffhausen, B. S., & Toker, A. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70444-0 · Cited by 608 · see citing works
Self-citationEssential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling
Ikenoue, T., Inoki, K., Yang, Q., Zhou, X., & Guan, K. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.119 · Cited by 605 · see citing works
Facchinetti, V., Ouyang, W., Wei, H., Soto, N., Lazorchak, A. S., Gould, C. M., Lowry, C. J., Newton, A. C., Mao, Y., Miao, Q., et al. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.120 · Cited by 508 · see citing works
Self-citationProtein kinase C is regulated in vivo by three functionally distinct phosphorylations
Keranen, L. M., Sonnenburg, E. D., & Newton, A. C. (1995) · Current Biology · doi:10.1016/s0960-9822(95)00277-6 · Cited by 470 · see citing works
Self-citationMolecular Mechanism for the Regulation of Protein Kinase B/Akt by Hydrophobic Motif Phosphorylation
Yang, J., Cron, P. D., Thompson, V., Good, V. M., Heß, D., Hemmings, B. A., & Barford, D. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00550-6 · Cited by 418 · see citing works
THE SELECTION OF S. CEREVISIAE MUTANTS DEFECTIVE IN THE START EVENT OF CELL DIVISION
Reed, S. I. (1980) · Genetics · doi:10.1093/genetics/95.3.561 · Cited by 393 · see citing works
Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1)
Sonnenburg, E. D., Toker, A., & Newton, A. C. (1998) · Current Biology · doi:10.1016/s0960-9822(98)00017-7 · Cited by 381 · see citing works
Self-citationA novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells
Zhang, T., Hamza, A., Cao, X., Wang, B., Yu, S., Zhan, C., & Sun, D. (2008) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-07-0484 · Cited by 364 · see citing works
High HSP90 Expression Is Associated with Decreased Survival in Breast Cancer
Pick, E., Kluger, Y., Giltnane, J. M., Moeder, C. B., Camp, R. L., Rimm, D. L., & Kluger, H. M. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4511 · Cited by 357 · see citing works
Xu, W., Mimnaugh, E. G., Rosser, M. F. N., Nicchitta, C. V., Marcu, M. G., Yarden, Y., & Neckers, L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m006864200 · Cited by 350 · see citing works
Akt-regulated pathways in prostate cancer
Majumder, P. K., & Sellers, W. R. (2005) · Oncogene · doi:10.1038/sj.onc.1209096 · Cited by 343 · see citing works
Structure of an Hsp90-Cdc37-Cdk4 Complex
Vaughan, C. K., Gohlke, U., Sobott, F., Good, V. M., Ali, M. M. U., Prodromou, C., Robinson, C. V., Saibil, H. R., & Pearl, L. H. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.07.016 · Cited by 293 · see citing works
Therapeutic and diagnostic implications of Hsp90 activation
Kamal, A., Boehm, M. F., & Burrows, F. J. (2004) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2004.04.006 · Cited by 280 · see citing works
Frödin, M., Antal, T. L., Dümmler, B. A., Jensen, C. J., Deak, M., Gammeltoft, S., & Biondi, R. M. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf551 · Cited by 275 · see citing works
Hsp90 and Cdc37 – a chaperone cancer conspiracy
Pearl, L. H. (2004) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2004.12.011 · Cited by 241 · see citing works
Kannan, N., Haste, N. M., Taylor, S. S., & Neuwald, A. F. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0610251104 · Cited by 236 · see citing works
Self-citationHsp90 Recognizes a Common Surface on Client Kinases
Citri, A., Harari, D., Shohat-Ophir, G., Ramakrishnan, P., Gan, J., Lavi, S., Eisenstein, M., Kimchi, A., Wallach, D., Pietrokovski, S., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m512613200 · Cited by 222 · see citing works
The Phosphatase PHLPP Controls the Cellular Levels of Protein Kinase C
Gao, T., Brognard, J., & Newton, A. C. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m707319200 · Cited by 211 · see citing works
Self-citationInvolvement of Hsp90 in Signaling and Stability of 3-Phosphoinositide-dependent Kinase-1
Fujita, N., Sato, S., Ishida, A., & Tsuruo, T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m106736200 · Cited by 198 · see citing works
Bornancin, F., & Parker, P. J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.6.3544 · Cited by 191 · see citing works
Molecular chaperones and protein kinase quality control
Caplan, A. J., Mandal, A. K., & Theodoraki, M. A. (2006) · Trends in Cell Biology · doi:10.1016/j.tcb.2006.12.002 · Cited by 185 · see citing works
Orr, J. W., Keranen, L. M., & Newton, A. C. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)49525-2 · Cited by 184 · see citing works
Self-citationXu, Y., Singer, M. A., & Lindquist, S. L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.1.109 · Cited by 184 · see citing works
Interaction between Src and a C-terminal Proline-rich Motif of Akt Is Required for Akt Activation
Jiang, T., & Qiu, Y. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212525200 · Cited by 179 · see citing works
Dries, D. R., Gallegos, L. L., & Newton, A. C. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.c600268200 · Cited by 159 · see citing works
Self-citationEDWARDS, A. S., & Newton, A. C. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.29.18382 · Cited by 153 · see citing works
Self-citationBehn-Krappa, A., & Newton, A. C. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80332-7 · Cited by 151 · see citing works
Self-citationThe Life and Death of Protein Kinase C
Gould, C. M., & Newton, A. C. (2008) · Current Drug Targets · doi:10.2174/138945008785132411 · Cited by 146 · see citing works
Self-citationTargeting the oncogene and kinome chaperone CDC37
Gray, P. J., Prince, T. L., Cheng, J., Stevenson, M. A., & Calderwood, S. K. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2420 · Cited by 136 · see citing works
The Turn Motif Is a Phosphorylation Switch That Regulates the Binding of Hsp70 to Protein Kinase C
Gao, T., & Newton, A. C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204335200 · Cited by 134 · see citing works
Self-citationStandaert, M. L., Bandyopadhyay, G. K., Kanoh, Y., Sajan, M. P., & Farese, R. V. (2000) · Biochemistry · doi:10.1021/bi0018234 · Cited by 133 · see citing works
HSP90 as a marker of progression in melanoma
McCarthy, M. M., Pick, E., Kluger, Y., Gould-Rothberg, B., Lazova, R. Z., Camp, R. L., Rimm, D. L., & Kluger, H. M. (2007) · Annals of Oncology · doi:10.1093/annonc/mdm545 · Cited by 127 · see citing works
Edwards, A., Faux, M. C., Scott, J. D., & Newton, A. C. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.10.6461 · Cited by 126 · see citing works
Self-citationSonnenburg, E. D., Gao, T., & Newton, A. C. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m107416200 · Cited by 117 · see citing works
Self-citationGrodsky, N. B., Li, Y., Bouzida, D., et al. (2006) · Biochemistry · doi:10.1021/bi061128h · Cited by 117 · see citing works
p23, a simple protein with complex activities
Felts, S. J., & Toft, D. O. (2003) · Cell Stress and Chaperones · doi:10.1379/1466-1268(2003)008 · Cited by 116 · see citing works
Rapamycin-sensitive phosphorylation of PKC on a carboxy-terminal site by an atypical PKC complex.
Ziegler, W., Parekh, D., Good, J. A. L., Whelan, R. D. H., Kelly, J., Frech, M., Hemmings, B., & Parker, P. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80236-x · Cited by 113 · see citing works
Gao, T., Toker, A., & Newton, A. C. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101357200 · Cited by 108 · see citing works
Self-citationGray, P. J., Stevenson, M. A., & Calderwood, S. K. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-3162 · Cited by 107 · see citing works
Prediction of Cancer Driver Mutations in Protein Kinases
Torkamani, A., & Schork, N. J. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5283 · Cited by 101 · see citing works
Sonnenburg, E. D., & Newton, A. C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.14.10697 · Cited by 97 · see citing works
Self-citationMoriwaki, Y., Kim, Y., Ido, Y., Misawa, H., Kawashima, K., Endo, S., & Takahashi, R. (2008) · Neuroscience Research · doi:10.1016/j.neures.2008.01.006 · Cited by 90 · see citing works
PKC alpha protein but not kinase activity is critical for glioma cell proliferation and survival
Cameron, A. J. M., Procyk, K. J., Leitges, M., et al. (2008) · International Journal of Cancer · doi:10.1002/ijc.23560 · Cited by 67 · see citing works
Cdc37 Regulation of the Kinome: When to Hold ‘Em and When to Fold ‘Em
Karnitz, L. M., & Felts, S. J. (2007) · Science s STKE · doi:10.1126/stke.3852007pe22 · Cited by 47 · see citing works
Protein Kinase C in Disease: Cancer
Fields, A. P., & Gustafson, W. C. (2003) · Humana Press eBooks · doi:10.1385/1-59259-397-6:519 · Cited by 42 · see citing works
Gao, T., & Newton, A. C. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m604076200 · Cited by 37 · see citing works
Self-citationKane, L., Mollenauer, M. N., & Weiss, A. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.9.5441 · Cited by 31 · see citing works
Stimulus-induced phosphorylation of PKC θ at the C-terminal hydrophobic-motif in human T lymphocytes
Freeley, M., Volkov, Y., Kelleher, D. P., et al. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.06.136 · Cited by 29 · see citing works
Yeong, S. S., Zhu, Y., Smith, D. J., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m511278200 · Cited by 20 · see citing works
Jane, E. P., & Pollack, I. F. (2008) · Cancer Letters · doi:10.1016/j.canlet.2008.03.039 · Cited by 19 · see citing works
Sánchez (2002) · doi:10.1379/1466-1268(2002)007
Flagged first, then by citations
Research works printed but not linked: 4
- Xu, Y., Singer, M. A., and Lindquist, S. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 109 -114
- Sato, S., Fujita, N., and Tsuruo, T. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 10832-10837
- Kannan, N., Haste, N., Taylor, S. S., and Neuwald, A. F. (2007) Proc. Natl. Acad. Sci. U. S. A. 104, 1272-1277
- Campbell, R. E., Tour, O., Palmer, A. E., Steinbach, P. A., Baird, G. S., Zacharias, D. A., and Tsien, R. Y. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 7877-7882
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Li, J., Soroka, J., & Buchner, J. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.09.003 · Cited by 498 · see citing works
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“In S. cerevisiae, expression of one of the two partially redundant genes encoding the essential (1,3)-bD-glucan synthase activity, FKS2, is regulated by both PKC signaling and calcineurin [46,47].”
BackgroundInfluentialLaFayette, S. L., Collins, C., Zaas, A. K., Schell, W. A., Betancourt-Quiroz, M., Gunatilaka, A. A. L., Perfect, J. R., & Cowen, L. E. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1001069 · Cited by 329 · see citing works
Caplan, T., Polvi, E. J., Xie, J. L., Buckhalter, S., Leach, M. D., Robbins, N., & Cowen, L. E. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.04.084 · Cited by 56 · see citing works
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- Authors
- Gould, C. M., Kannan, N., Taylor, S. S., & Newton, A. C.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Newton, Alexandra C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-02
- Volume
- 284
- Issue
- 8
- Pages
- 4921-4935
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2643500
- OpenAlex
- W2106835772
- Cited by
- 113
- References
- 62
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2023: 3 · 2022: 6 · 2021: 2 · 2020: 2 · 2019: 6 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 9 · 2014: 10 · 2013: 10 · 2012: 10
- FWCI
- 4.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (P01 DK54441, DK54441)
- National Institute of General Medical Sciences (2T32 GM07752, T32GM007752, GM 43154)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK054441, P01DK54441)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- protein kinase C, HSP90, Cdc37, PXXP motif, C-terminal tail, protein maturation, chaperone binding, molecular clamp, PKCβII, PKC isoforms, protein stability, AGC kinases, Hsp90 inhibitors
- MeSH terms
- Animals, Carrier Proteins, Chlorocebus aethiops, Enzyme Stability, HeLa Cells, Humans, Isoenzymes, Models, Molecular, Phosphorylation, Protein Binding, Protein Kinase C, Protein Structure, Tertiary, Cell Cycle Proteins, Chaperonins, HSP90 Heat-Shock Proteins, COS Cells, Amino Acid Substitution, Mutation, Missense, Amino Acid Motifs, Rats, Hydrophobic and Hydrophilic Interactions, Protein Kinase C beta
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