Functions of the Hsp90-Binding FKBP Immunophilins - The Networking of Chaperones by Co-chaperones - page 55

Han et al. 2006 ). Interestingly, overexpression of related FKBP proteins in tu-
mors is associated with a poor treatment outcome and prognosis (Romano et al.
2010 ; Solassol et al. 2011 ). Conversely, increased levels of FKBPL correlate to
a more positive response to treatment and a more favorable prognosis (McKeen
et al. 2010 ; McKeen et al. 2011 ; Han et al. 2006 ). FKBPL stability is regulated
by RBCK1, and as with FKBPL, RBCK1 is up-regulated by estrogen and can
interact with the FKBPL/ER/Hsp90 complex (Donley et al. 2013 ). Increased ex-
pression of both FKBPL and RBCK1 appear to correlate with increased survival;
however, elevated RBCK1 levels reduce the efficacy of tamoxifen (Donley et al.
2013 ). The interactions leading to tumor survival and progression still need to be
explored further.
Finally, FKBPL possesses anti-angiogenic properties (Yakkundi et al. 2013 ). In
a mouse xenograft tumor model overexpression of FKBPL resulted in decreased
tumor growth and tumor necrosis (Crabb et al. 2009 ). The anti-angiogenic effects
of FKBPL are mediated through the N-terminal portion of the protein comprised of
amino acids 34-58, termed peptide AD-01, which is currently being explored as a
novel anti-angiogenic drug (Valentine et al. 2011 ; Yakkundi et al. 2013 ).
Plant FKBPs
Hsp90-binding TPR immunophilins have been identified in all eukaryotes exam-
ined. A few examples of plant TPR-containing FKBPs are shown in Fig. 2.1 . The
TPR domain of each FKBP is very similar in amino acid sequence to that of verte-
brate proteins; these are presumed to bind Hsp90, but that has not been determined
in all cases. The plant and insect FKBPs contain one or more PPIase-related domain
and can contain other functional domains. For example, AtFKBP42 contains a C-
terminal transmembrane domain that localizes the protein to the inner plasma mem-
brane and the vacuolar membrane (Kamphausen et al. 2002 ; Geisler et al. 2003 ;
Geisler et al. 2004 ).
There is ample evidence to suggest that the plant and insect FKBPs are physi-
ologically important. Mutations in AtFKBP42 cause the severe developmental
phenotypes termed twisted dwarf 1 (TWD) (Geisler et al. 2003 ) and ultracurvata
(UCU2) (Perez-Perez et al. 2004 ). The mechanism by which these phenotypes
occur likely involves impairment of membrane transport of the growth hormone
auxin, as AtFKBP42 is known to interact with several ATP-binding cassette
transporters on the plasma and vacuolar membranes (Geisler et al. 2004 ; Geisler
et al. 2003 ; Liu et al. 2001 ). Mutations in AtFKBP72 result in a class of mutants
termed pasticcino or pas mutants, which are characterized by a wide variety of
developmental defects (Vittorioso et al. 1998 ). Two Hsp90-binding TPR FKBPs
in wheat, wFKBP72 and the heat shock-inducible wFKBP77, have been shown
in transgenic plants to distinctively influence developmental patterns (Kurek
et al. 2002 ).