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Gene Review

CDC37  -  cell division cycle 37

Homo sapiens

Synonyms: CDC37A, Hsp90 chaperone protein kinase-targeting subunit, Hsp90 co-chaperone Cdc37, P50CDC37, p50Cdc37
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Disease relevance of CDC37


High impact information on CDC37

  • Inactive Raf is found in the cytosol in a complex with Hsp90, Hsp50 (Cdc37) and the 14-3-3 proteins [6].
  • Recruitment of protein kinase clients to the Hsp90 chaperone system is mediated by the cochaperone adaptor protein Cdc37, which acts as a scaffold, simultaneously binding protein kinases and Hsp90 [7].
  • We identify Cdc37 and Hsp90 as two additional components of the IKK complex [8].
  • Our studies demonstrate that Cdc37 has a general role in kinome biogenesis [9].
  • This degradation phenotype was suppressed when cdc37 mutant cells were grown at reduced temperatures, although this did not lead to a full restoration of kinase activity [9].

Biological context of CDC37


Anatomical context of CDC37

  • In this report, we demonstrate that mammalian Cdc37 is phosphorylated on Ser13 in situ in rabbit reticulocyte lysate and in cultured K562 cells and that casein kinase II is capable of quantitatively phosphorylating recombinant Cdc37 at this site [12].
  • These studies show that nascent EGFRvIII in the endoplasmic reticulum associates with Hsp90 and Cdc37, and that the Hsp90 association is necessary to maintain expression of EGFRvIII [13].
  • Such an event, occurring within 10-30 min of the addition of TCDD, is also accompanied by simultaneous translocation of both Src and cdc37 proteins from cytosol into the 100,000 x g membrane fraction containing the plasma membrane [14].
  • In addition, cell fractionation data indicate that Cdc37 is found in caveolae with eNOS [15].
  • In the present study, we demonstrate by coimmunoprecipitation and affinity purification in bovine aortic endothelial cells (BAECs) that Cdc37 is complexed with eNOS, Hsp90, and Akt [15].

Associations of CDC37 with chemical compounds

  • Mutation of either glycine at the equivalent positions of Raf1 (G358A and G361A) also inhibited Cdc37 binding to Raf1 [10].
  • Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37 [12].
  • Mutant constructs containing deletions of secondary structural elements from the N- and C-termini of Cdk2 were prepared and assayed for their ability to coadsorb Hsp90 and Cdc37 in a salt-stable high-affinity manner with and without the addition of molybdate [16].
  • In addition, a nonclient kinase, the catalytic subunit of cyclic AMP-dependent protein kinase, interacts with Cdc37 but only when a threonine residue in the activation segment of its C lobe is unphosphorylated [17].
  • In this report, the crystal structure of the Src family tyrosine kinase Lck was used to guide the creation of kinase constructs to determine features recognized by Hsp90 and its "kinase-specific" co-chaperone Cdc37 [18].

Physical interactions of CDC37

  • We first determined, using in vitro assays, that Cdc37 binds to the amino-terminal lobe of Cdk4 [10].
  • A series of Cdc37 deletion mutants revealed that all mutants capable of binding Raf-1 possess amino acid residues between 181 and 200 [11].
  • Collectively, our results demonstrate that the Hsp90/Cdc37 complex is a major regulator of the stability of the LKB1 tumor suppressor [4].
  • 1H, 13C and 15N backbone resonance assignment of the Hsp90 binding domain of human Cdc37 [19].
  • Additionally, scanning alanine mutagenesis identified four amino acid residues at the N-terminus of Cdc37 that are critical for high-affinity binding of Cdc37 to client HRI molecules [20].

Regulatory relationships of CDC37

  • Importantly, overexpression of Cdc37 not only stimulated cyclin D1 binding to wild type Cdk4 but also restored its binding to Cdk4(G15A) [10].

Other interactions of CDC37

  • Replacing another conserved residue critical for ATP binding and kinase activity, Lys-35 (K35A), reduced Cdc37-Cdk4 complex formation but to a lesser extent [10].
  • Cdc37 is a molecular chaperone that is important for the stability and activity of several protein kinases, including Cdk4 and Raf1 [10].
  • Subsequently, pull-down assays directed at helix alphaC of Cdk2 are shown to disrupt Hsp90 and Cdc37 binding and explain the initial difficulties in demonstrating these interactions [16].
  • Harc was also found to heterodimerize with Cdc37 in vitro [21].
  • In this report, crystal structures of protein kinases were used to guide the dissection of two kinases [the Src-family tyrosine kinase, Lck, and the heme-regulated eIF2alpha kinase (HRI)], and the association of Hsp90 and Cdc37 with these constructs was assessed [22].

Analytical, diagnostic and therapeutic context of CDC37

  • Real-time RT-PCR showed that the expression of CDC37 gene was significantly up-regulated in MM patients with cyclin D1 overexpression compared with those without it (p=0.0418) [23].
  • Titration experiments revealed that Harc homodimerization was favored over heterodimerization with Cdc37 when both cochaperones were at similar levels [21].
  • Functional dissection of cdc37: characterization of domain structure and amino acid residues critical for protein kinase binding [20].


  1. Role of HSP90, CDC37, and CRM1 as modulators of P16(INK4A) activity in rat liver carcinogenesis and human liver cancer. Pascale, R.M., Simile, M.M., Calvisi, D.F., Frau, M., Muroni, M.R., Seddaiu, M.A., Daino, L., Muntoni, M.D., De Miglio, M.R., Thorgeirsson, S.S., Feo, F. Hepatology (2005) [Pubmed]
  2. Role of p50/CDC37 in hepadnavirus assembly and replication. Wang, X., Grammatikakis, N., Hu, J. J. Biol. Chem. (2002) [Pubmed]
  3. Induction of human Cdc37 in prostate cancer correlates with the ability of targeted Cdc37 expression to promote prostatic hyperplasia. Stepanova, L., Yang, G., DeMayo, F., Wheeler, T.M., Finegold, M., Thompson, T.C., Harper, J.W. Oncogene (2000) [Pubmed]
  4. Stability of the Peutz-Jeghers syndrome kinase LKB1 requires its binding to the molecular chaperones Hsp90/Cdc37. Nony, P., Gaude, H., Rossel, M., Fournier, L., Rouault, J.P., Billaud, M. Oncogene (2003) [Pubmed]
  5. The Platelet-derived Growth Factor Receptor {alpha} Is Destabilized by Geldanamycins in Cancer Cells. Matei, D., Satpathy, M., Cao, L., Lai, Y.C., Nakshatri, H., Donner, D.B. J. Biol. Chem. (2007) [Pubmed]
  6. A dimeric 14-3-3 protein is an essential cofactor for Raf kinase activity. Tzivion, G., Luo, Z., Avruch, J. Nature (1998) [Pubmed]
  7. Structure of an Hsp90-Cdc37-Cdk4 complex. Vaughan, C.K., Gohlke, U., Sobott, F., Good, V.M., Ali, M.M., Prodromou, C., Robinson, C.V., Saibil, H.R., Pearl, L.H. Mol. Cell (2006) [Pubmed]
  8. TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90. Chen, G., Cao, P., Goeddel, D.V. Mol. Cell (2002) [Pubmed]
  9. Cdc37 has distinct roles in protein kinase quality control that protect nascent chains from degradation and promote posttranslational maturation. Mandal, A.K., Lee, P., Chen, J.A., Nillegoda, N., Heller, A., Distasio, S., Oen, H., Victor, J., Nair, D.M., Brodsky, J.L., Caplan, A.J. J. Cell Biol. (2007) [Pubmed]
  10. Identification of a conserved sequence motif that promotes Cdc37 and cyclin D1 binding to Cdk4. Zhao, Q., Boschelli, F., Caplan, A.J., Arndt, K.T. J. Biol. Chem. (2004) [Pubmed]
  11. A client-binding site of Cdc37. Terasawa, K., Minami, Y. FEBS J. (2005) [Pubmed]
  12. Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. Shao, J., Prince, T., Hartson, S.D., Matts, R.L. J. Biol. Chem. (2003) [Pubmed]
  13. Interaction of Hsp90 with the nascent form of the mutant epidermal growth factor receptor EGFRvIII. Lavictoire, S.J., Parolin, D.A., Klimowicz, A.C., Kelly, J.F., Lorimer, I.A. J. Biol. Chem. (2003) [Pubmed]
  14. Rapid activation of c-Src kinase by dioxin is mediated by the Cdc37-HSP90 complex as part of Ah receptor signaling in MCF10A cells. Park, S., Dong, B., Matsumura, F. Biochemistry (2007) [Pubmed]
  15. Direct interaction of the cell division cycle 37 homolog inhibits endothelial nitric oxide synthase activity. Harris, M.B., Bartoli, M., Sood, S.G., Matts, R.L., Venema, R.C. Circ. Res. (2006) [Pubmed]
  16. Cdk2: a genuine protein kinase client of Hsp90 and Cdc37. Prince, T., Sun, L., Matts, R.L. Biochemistry (2005) [Pubmed]
  17. Cdc37 interacts with the glycine-rich loop of Hsp90 client kinases. Terasawa, K., Yoshimatsu, K., Iemura, S., Natsume, T., Tanaka, K., Minami, Y. Mol. Cell. Biol. (2006) [Pubmed]
  18. Definition of protein kinase sequence motifs that trigger high affinity binding of Hsp90 and Cdc37. Prince, T., Matts, R.L. J. Biol. Chem. (2004) [Pubmed]
  19. 1H, 13C and 15N backbone resonance assignment of the Hsp90 binding domain of human Cdc37. Sreeramulu, S., Kumar, J., Richter, C., Vogtherr, M., Saxena, K., Langer, T., Schwalbe, H. J. Biomol. NMR (2005) [Pubmed]
  20. Functional dissection of cdc37: characterization of domain structure and amino acid residues critical for protein kinase binding. Shao, J., Irwin, A., Hartson, S.D., Matts, R.L. Biochemistry (2003) [Pubmed]
  21. Domain-mediated dimerization of the Hsp90 cochaperones Harc and Cdc37. Roiniotis, J., Masendycz, P., Ho, S., Scholz, G.M. Biochemistry (2005) [Pubmed]
  22. High affinity binding of Hsp90 is triggered by multiple discrete segments of its kinase clients. Scroggins, B.T., Prince, T., Shao, J., Uma, S., Huang, W., Guo, Y., Yun, B.G., Hedman, K., Matts, R.L., Hartson, S.D. Biochemistry (2003) [Pubmed]
  23. Cyclin D1 overexpression is not a specific grouping marker, but may collaborate with CDC37 in myeloma cells. Katayama, Y., Sakai, A., Okikawa, Y., Oue, N., Asaoku, H., Sasaki, A., Imanaka, F., Tsujimoto, T., Takimoto, Y., Masuda, R., Nakaju, N., Otsuki, T., Yasui, W., Kimura, A. Int. J. Oncol. (2004) [Pubmed]
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