The Essence of the Hippo Signalling System - Therapeutic Strategies in Cancer Biology and Pathology - page 142

firmly allied Kibra with the regulation of cell proliferation (Xiao et al., 2011). Kibra
seems to generate its suppressive effects in collaboration with Merlin with which it
forms a complex and this complex regulates Hippo signalling. The formation of this
complex is related to the phosphorylation of Kibra, possibly of the Ser539 by Aurora
kinase (Xiao et al., 2011; Yu et al., 2010). Although Kibra and Merlin have appeared
as two separate upstream regulatory components of the Hippo pathway, they indeed
seem to be functionally related. At the practical level, it is of considerable interest
that Kibra interacts and forms a complex with DYNLL1 (dynein light chain 1). The
Kibra/DYNLL1 complex might be important for the transactivation of ER (Rayala
et al., 2006). As discussed in several contexts, ER− and indeed TNBC form a formi-
dable challenge in breast cancer treatment.
One might recall here that DYNLL1 is a participant in several biological functions,
especially with regard to apoptosis by abolishing the anti-apoptotic activity of Bcl-2.
DYNLL1 might also regulate apoptosis by other means. It is said to interact with Dkk
(Dickkopf)-3 (Ochiai et al., 2011). Dkks inhibit Wnt signalling and obviously interac-
tion between Dkk and DYNLL1 might have implications for apoptosis and activation
of EMT. Zhang et al. (2008c) found DYNLL1 interacted with RACK1 and BimEL a
pro-apoptosis protein of the Bcl-2 family. RACK1 has been postulated to interact with
integrin and in this way inhibit cell motility (Buensuceso et al., 2001). DYNLL1 is a
component of the dynein complex and is a substrate for PAK1 serine/threonine kinase
which participates in cell proliferation, migration and morphogenesis. PAK1 modulates
the actin cytoskeleton, and cytoskeletal dynamics are also influenced by the dynein
complex and so they are functionally tightly related. As noted before, Merlin is also a
substrate for PAK. The obvious phosphorylation-mediated functional linkup between
Kibra and Merlin could be theoretically meaningful and important.
Kibra is hypermethylated in leukaemias. Methylation has been encountered in
70% of B-ALL (acute lymphocytic leukaemia), in <20% T-ALL and in around a
third of CLL (chronic lymphocytic leukaemia) patients. Of much interest also is the
finding that methylation was not seen in remission. The methylated status reflected
poor prognosis for CLL patients (Hill et al., 2011; Shinawi et al., 2012).
Kibra methylation may be potentially regarded as relevant to the pathogenetic
process since it was associated in ALL with the chromosomal translocation t(12;21)
(p13;q22) involving ETV6/RUNX1 commonly associated with childhood ALL.
RASSF Family Suppressor Genes
RASSF family genes are upstream regulators of Hippo signalling. RASSF are so called
because they contain the RA (Ras-association domain). Several members of the fam-
ily are known. The presence of two sub-groups has been acknowledged. RASSF1-
RASSF6 (the C-terminal family) carry the RA domain at the C-terminus while
the domain occurs at the N-terminus in N-terminal family of RASSF7-RASSF10.
The RA domain mediates RASSF binding to GTPases. But they probably differen-
tially interact with Ras proteins in vitro (Ikeda et al., 2007). The SARAH domain is
also an important motif of RASSFs. SARAH occurs immediately C-terminal to the
RA domain in RASSF1-RASSF6. The N-terminal family RASSFs lack the SARAH