The Essence of the Hippo Signalling System - Therapeutic Strategies in Cancer Biology and Pathology - page 143

RTK

Ras GDP Ras GTP

RASSFs

Pro-apoptosis
Bcl-2 family gene MAPK PI3K/Akt

MKK

Hippo kinases
MST1/ MST2

Caspases

JNK Anti-apoptosis

Bcl-2 family
genes

Apoptosis

Figure 25.2 The signalling pathways mediated by RASSF proteins in the induction of
apoptosis. Four postulated pathways shown include caspase-mediated function of pro-
apoptosis Bcl-2 genes or PI3K/Akt-mediated inhibition of anti-apoptosis genes. Akt is
also suggested to phosphorylate and activate the Hippo kinases and Hippo also might act
independently of Akt-mediated activation. RASSF can also activate MAPK/MKK and
pro-apoptotic JNK pathway.

domain (Weyden and Adams, 2007; Richter et al., 2009). The SARAH domain facili-
tates the heterodimerisation of RASSFs with the Hippo kinases MST1 and MST2. In
general, RASSFs are suppressors of tumorigenesis, cell proliferation and regulation
of the cell cycle and inducers of apoptosis. Some members may be involved with the
stabilisation of cytoskeletal structures (Sherwood et al., 2010). RASSF function is
regulated by the phosphorylation of amino acid residues of the RA domain (Richter
et al., 2010). However, at present, there is no clarity of distinction in function between
the C-terminal and N-terminal RASSFs (but see below). The postulated pathways of
RASS signalling are shown in Figure 25.2 which has to be read in conjunction with
Figure 25.1 depicting the Hippo signalling and interacting pathways.

RASSF Genes Are Silenced in Tumours

This gene family has received much attention on account of frequent methylation and
inactivation of its members in many human neoplasms, for example epithelial can-
cers, leukaemia and lymphomas and several forms of childhood cancers, so much so
they have been widely described as tumour suppressor genes. The C-terminal RASSFs
might be tumour suppressors, but the N-terminal RASSFs are not (see below). The
degree of methylation might vary and some RASSF genes might be prominently meth-
ylated as in neuroblastomas where RASSF7 has been conspicuous in its frequency of