Cdc37 as a Co-chaperone to Hsp90 - The Networking of Chaperones by Co-chaperones - page 106

Nishida 2005 ). CK2 phosphorylates Cdc37 on serine 13, a modification with pro-
found impact on function, leading to formation of stable complexes with the clients
(Miyata and Nishida 2005 ). In addition CK2 phosphorylates Hsp90 on threonine
(T) 22 in yeast (human T36), an interaction that stabilizes binding to co-chaperones
Cdc37 and Aha1 (Mollapour et al. 2011 ). CK2 is thus a key enzyme in Hsp90/
Cdc37 client folding. Recently it has been shown that tyrosine (Y) phosphoryla-
tion also has profound effects on Hsp90/Cdc37 activities. Cdc37 phosphorylation
on Y4 and Y298 disrupts client association while Hsp90 phosphorylation on Y197
leads to dissociation of Cdc37. (Xu et al. 2012 ; Xu and Neckers 2012 ) The enzyme
implicated in these modifications is the non-receptor tyrosine kinase Yes (Summy
et al. 2003 ; Xu et al. 2012 ). The findings thus suggest profound regulation of each
step of the Cdc37/Hsp90 chaperoning cycle by PTMs.
Cdc37 in Cell Proliferation and Cancer
As a cell cycle division protein, required to drive cell proliferation, it is probably not
surprising that CDC37 appears to play a positive role in tumorigenesis (Gray et al.
2008 ; Stepanova et al. 2000a ). An early hint suggesting such a role was provided
by the finding of a requirement for Cdc37, along with Hsp90 in the transforming
functions of the viral oncogene p60v-src (Dey et al. 1996 ; Perdew et al. 1997 ).
More conclusive evidence for a transforming role for Cdc37 was next provided by
the finding that overexpression of the cdc37 gene in transgenic mice could lead to
elevated rates of prostate tumorigenesis, a process that was amplified by co-expres-
sion of the proto-oncogene c-Myc (Stepanova et al. 2000b ). Subsequently other
cancer types such as anaplastic large cell lymphoma, acute myeloblastic leukemia,
multiple myeloma and hepatocellular carcinoma have been shown to express high
levels of cdc37 (rev.) (Gray et al. 2008 ). The exact upstream mediator of Cdc37
tumorigenesis might be currently difficult to tie down due to the large numbers
of potential Hsp90/CDc37 targets with potential roles in carcinogenesis. Probable
candidates could include: (1) Activity of the androgen receptor (AR) (Heinlein and
Chang 2004 ). While most steroid hormone receptors require Hsp90 for optimal
folding and activity, only AR has been shown to be dependent on Cdc37 (Fliss et al.
1997 ; Rao et al. 2001 ). Indeed Cdc37 knockdown in AR + LnCaP cells was shown
to lead to the loss of androgen-dependent AR-mediated transcriptional activity and
to a reduction in target PSA expression (Gray et al. 2007 ). It may be significant that
Cdc37 has been found to be associated with the AR co-activating protein Vav3 (Wu
et al. 2013 ). Disruption of AR-Vav3 interactions inhibited the co-activating effects
of Vav3 (Wu et al. 2013 ). AR has been shown to be essential for the early stages
in prostate tumorigenesis and to even play unpredicted roles in castration-resistant
forms of PCa. Thus a role for Cdc37 in fostering AR activity and prostate carci-
nogenesis might be postulated. However other promising candidates for CDC37
targets exist. Protein kinases are the preferred clients of Cdc37 and upward of 50 %