Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Targeting the oncogene and kinome chaperone CDC37


CDC37 is a molecular chaperone that physically stabilizes the catalytic domains found in protein kinases and is therefore a wide-spectrum regulator of protein phosphorylation. It is also an overexpressed oncoprotein that mediates carcinogenesis by stabilizing the compromised structures of mutant and/or overexpressed oncogenic kinases. Recent work shows that such dependency of malignant cells on increased CDC37 expression is a vulnerability that can be targeted in cancer by agents that deplete or inhibit CDC37. CDC37 is thus a candidate for broad-spectrum molecular cancer therapy.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Interaction domains in CDC37.
Figure 2: Effects of CDC37 depletion on anabolic signalling and cell stress pathways.
Figure 3: Contrasting effects of targeting HSP90 and CDC37.


  1. 1

    Whitesell, L. & Lindquist, S. L. HSP90 and the chaperoning of cancer. Nature Rev. Cancer 5, 761–772 (2005).

    CAS  Article  Google Scholar 

  2. 2

    Pearl, L. H. Hsp90 and Cdc37 — a chaperone cancer conspiracy. Curr. Opin. Genet. Dev. 15, 55–61 (2005).

    CAS  Article  Google Scholar 

  3. 3

    Calderwood, S. K., Khaleque, M. A., Sawyer, D. B. & Ciocca, D. R. Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem. Sci. 31, 164–172 (2006).

    CAS  Article  Google Scholar 

  4. 4

    Neckers, L. & Ivy, S. P. Heat shock protein 90. Curr. Opin. Oncol. 15, 419–424 (2003).

    CAS  Article  Google Scholar 

  5. 5

    Workman, P. Altered states: selectively drugging the Hsp90 cancer chaperone. Trends Mol. Med. 10, 47–51 (2004).

    CAS  Article  Google Scholar 

  6. 6

    Stepanova, L. et al. Induction of human Cdc37 in prostate cancer correlates with the ability of targeted Cdc37 expression to promote prostatic hyperplasia. Oncogene 19, 2186–2193 (2000).

    CAS  Article  Google Scholar 

  7. 7

    Vaughan, C. K. et al. Structure of an Hsp90–Cdc37–Cdk4 complex. Mol. Cell 23, 697–707 (2006).

    CAS  Article  Google Scholar 

  8. 8

    Caplan, A. J., Ma'ayan, A. & Willis, I. M. Multiple kinases and system robustness: a link between Cdc37 and genome integrity. Cell Cycle 6, 3145–3147 (2007).

    CAS  Article  Google Scholar 

  9. 9

    Caplan, A. J., Mandal, A. K. & Theodoraki, M. A. Molecular chaperones and protein kinase quality control. Trends Cell Biol. 17, 87–92 (2007).

    CAS  Article  Google Scholar 

  10. 10

    Mandal, A. K. et al. Cdc37 has distinct roles in protein kinase quality control that protect nascent chains from degradation and promote posttranslational maturation. J. Cell Biol. 176, 319–328 (2007).

    CAS  Article  Google Scholar 

  11. 11

    Reed, S. I. The selection of S. cerevisiae mutants defective in the start event of cell division. Genetics 95, 561–577 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Pascale, R. M. et al. Role of HSP90, CDC37, and CRM1 as modulators of P16INK4A activity in rat liver carcinogenesis and human liver cancer. Hepatology 42, 1310–9 (2005).

    CAS  Article  Google Scholar 

  13. 13

    Prince, T., Sun, L. & Matts, R. L. Cdk2: a genuine protein kinase client of Hsp90 and Cdc37. Biochemistry 44, 15287–15295 (2005).

    CAS  Article  Google Scholar 

  14. 14

    Stepanova, L., Finegold, M., DeMayo, F., Schmidt, E. V. & Harper, J. W. The oncoprotein kinase chaperone CDC37 functions as an oncogene in mice and collaborates with both c-myc and cyclin D1 in transformation of multiple tissues. Mol. Cell Biol. 20, 4462–4473 (2000).

    CAS  Article  Google Scholar 

  15. 15

    Schwarze, S. R., Fu, V. X. & Jarrard, D. F. Cdc37 enhances proliferation and is necessary for normal human prostate epithelial cell survival. Cancer Res. 63, 4614–4619 (2003).

    CAS  PubMed  Google Scholar 

  16. 16

    Robzyk, K. et al. Uncoupling of hormone-dependence from chaperone-dependence in the L701H mutation of the androgen receptor. Mol. Cell. Endocrinol. 268, 767–774 (2007).

    Article  Google Scholar 

  17. 17

    Shao, J., Prince, T., Hartson, S. D. & Matts, R. L. Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. J. Biol. Chem. 278, 38117–38120 (2003).

    CAS  Article  Google Scholar 

  18. 18

    Miyata, Y. & Nishida, E. CK2 binds, phosphorylates, and regulates its pivotal substrate Cdc37, an Hsp90-cochaperone. Mol. Cell Biochem. 274, 171–179 (2005).

    CAS  Article  Google Scholar 

  19. 19

    Turnbull, E. L., Martin, I. V. & Fantes, P. A. Cdc37 maintains cellular viability in Schizosaccharomyces pombe independently of interactions with heat-shock protein 90. FEBS J. 272, 4129–4140 (2005).

    CAS  Article  Google Scholar 

  20. 20

    MacLean, M. & Picard, D. Cdc37 goes beyond Hsp90 and kinases. Cell Stress Chaperones 8, 114–119 (2003).

    CAS  Article  Google Scholar 

  21. 21

    Cox, M. B. et al. Fkbp52 phosphorylation: a potential mechanism for regulating steroid hormone receptor activity. Mol. Endocrinol. (2007).

  22. 22

    Prince, T. & Matts, R. L. Definition of protein kinase sequence motifs that trigger high affinity binding of Hsp90 and Cdc37. J. Biol. Chem. 279, 39975–39981 (2004).

    CAS  Article  Google Scholar 

  23. 23

    Prince, T. & Matts, R. L. Exposure of protein kinase motifs that trigger binding of Hsp90 and Cdc37. Biochem. Biophys. Res. Commun. 338, 1447–1454 (2005).

    CAS  Article  Google Scholar 

  24. 24

    Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002).

    CAS  Article  Google Scholar 

  25. 25

    Stepanova, L., Leng, X., Parker, S. B. & Harper, J. W. Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. Genes Dev. 10, 1491–502 (1996).

    CAS  Article  Google Scholar 

  26. 26

    Waza, M. et al. Modulation of Hsp90 function in neurodegenerative disorders: a molecular-targeted therapy against disease-causing protein. J. Mol. Med. 84, 635–646 (2006).

    CAS  Article  Google Scholar 

  27. 27

    Kamal, A. et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425, 407–410 (2003).

    CAS  Article  Google Scholar 

  28. 28

    Theodoraki, M. A., Kunjappu, M., Sternberg, D. W. & Caplan, A. J. Akt shows variable sensitivity to an Hsp90 inhibitor depending on cell context. Exp. Cell Res. (2007).

  29. 29

    Thompson, M. A. et al. Differential gene expression in anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative anaplastic large cell lymphomas. Hum. Pathol. 36, 494–504 (2005).

    CAS  Article  Google Scholar 

  30. 30

    Katayama, Y. et al. Cyclin D1 overexpression is not a specific grouping marker, but may collaborate with CDC37 in myeloma cells. Int. J. Oncol. 25, 579–595 (2004).

    CAS  PubMed  Google Scholar 

  31. 31

    Feo, F. et al. Hepatocellular carcinoma as a complex polygenic disease. Interpretive analysis of recent developments on genetic predisposition. Biochim. Biophys. Acta 1765, 126–147 (2006).

    CAS  PubMed  Google Scholar 

  32. 32

    Casas, S. et al. Changes in apoptosis-related pathways in acute myelocytic leukemia. Cancer Genet. Cytogenet. 146, 89–101 (2003).

    CAS  Article  Google Scholar 

  33. 33

    Gaboli, M. et al. Mzf1 controls cell proliferation and tumorigenesis. Genes Dev. 15, 1625–1630 (2001).

    CAS  Article  Google Scholar 

  34. 34

    Zou, J., Guo, Y., Guettouche, T., Smith, D. F. & Voellmy, R. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 94, 471–480 (1998).

    CAS  Article  Google Scholar 

  35. 35

    Gray, P. J. Jr, Stevenson, M. A. & Calderwood, S. K. Targeting Cdc37 inhibits multiple signaling pathways and induces growth arrest in prostate cancer cells. Cancer Res. 67, 11942–11950 (2007).

    CAS  Article  Google Scholar 

  36. 36

    Zaarur, N., Gabai, V. L., Porco, J. A. Jr, Calderwood, S. & Sherman, M. Y. Targeting heat shock response to sensitize cancer cells to proteasome and Hsp90 inhibitors. Cancer Res. 66, 1783–1791 (2006).

    CAS  Article  Google Scholar 

  37. 37

    Roiniotis, J., Masendycz, P., Ho, S. & Scholz, G. M. Domain-mediated dimerization of the Hsp90 cochaperones Harc and Cdc37. Biochemistry 44, 6662–6669 (2005).

    CAS  Article  Google Scholar 

  38. 38

    Holmes, J. L., Sharp, S. Y., Hobbs, S. & Workman, P. Silencing of HSP90 cochaperone AHA1 expression decreases client protein activation and increases cellular sensitivity to the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin. Cancer Res. 68, 1188–1197 (2008).

    Article  Google Scholar 

  39. 39

    Zhang, T. et al. A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells. Mol. Cancer Ther. 7, 162–170 (2008).

    CAS  Article  Google Scholar 

Download references


We acknowledge the support of the Department of Radiation Oncology at Beth Israel Deaconess Medical Center. These studies were also supported by National Institutes of Health grants 5RO1CA047407 and 3RO1CA094397 (S.K.C.) and a Howard Hughes Medical Institute Medical Student Research Training Fellowship (P.J.G.). Because of space limitations we were unable to cite many significant studies on CDC37 and HSP90. We apologize to the authors of such studies and refer the readers to excellent publications that cite the literature more inclusively (Refs 1,2,3,5,9,10

Author information



Corresponding author

Correspondence to Stuart K. Calderwood.

Related links

Related links


National cancer institute

anaplastic large cell lymphoma

hepatocellular carcinoma

multiple myeloma

prostate cancer


Didier Picard's list of CDC37 client kinases

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gray, P., Prince, T., Cheng, J. et al. Targeting the oncogene and kinome chaperone CDC37. Nat Rev Cancer 8, 491–495 (2008).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing