Cdc37 as a Co-chaperone to Hsp90 - The Networking of Chaperones by Co-chaperones - page 108

in protein quality control and longevity (Calderwood et al. 2009 ). Autophagy is
significant in protein homeostasis in that bulky protein aggregates or damaged or-
ganelles that cannot enter the lumen of the proteasome for proteolytic digestion can
be enveloped by autophagosomes and broken down (Calderwood et al. 2009 ). The
Cdc37-Hsp90 complex was shown to stabilizes and activate ULK1, a protein kinase
that phosphorylates Atg1 one of the first steps in initiating the autophagy pathway
and in this way regulated mitophagy, a specialize autophagy-like process involved
in breaking down damaged mitochondria (Joo et al. 2011 ). Cdc37-fostered autoph-
agy may be important in neurodegenerative diseases such as Amyotrophic Lateral
Sclerosis and Alzheimer disease, that are components of the aging process and
chaperone complexes may be involved in clearance of misfolded proteins through
the autophagy pathway (Jinwal et al. 2012 ).
Conclusions
Thus Cdc37, as a major component of the protein complex that controls the folding
of protein kinases in the cell stands at the hub of a multitude of intracellular signal-
ing networks (Caplan et al. 2007a ; Gray et al. 2008 ; Karnitz and Felts 2007 ). Its
effects thus reach beyond the housekeeping pathways of protein folding into a wide
range of cellular processes. Further developments may await more information as
to the exact role of Cdc37 in molecular chaperone function.
Due to its influence in cell growth pathways Cdc37 has attracted much attention
as a potential intermediate in carcinogenesis and indeed proof of concept studies in
cell lines indicate that Cdc37 is required for cancer cell signaling and that quench-
ing the influence of the co-chaperone prevents malignant cell growth (Gray et al.
2008 ). Cdc37 might be an attractive potential target in cancer due to (1) the fact that
it may be expressed to high level in some types of cancer and (2) controls multiple
signaling pathways. This indicates a potential for: (1) selectivity due to its elevated
expression and (2) robustness as the co-chaperone may control multiple growth sig-
naling pathways and may thus be less prone to evolution of resistance than for other
oncoproteins. Currently specific agents to target Cdc37 are not available.
Protein aggregation disorders have been linked to molecular chaperones and to
age related declines in molecular chaperones and co-chaperones (Calderwood et al.
2009 ). Cdc37 appears to be a potential agent in longevity due to its links to protein
folding and autophagy and it will be informative to study the role of Cdc37 main-
tenance/decline in aging organisms. The development of agents that might increase
Cdc37 levels may thus be called for to remedy aging relate shortfalls (Fig. 5.2 ).