RKIP Suppresses Invasion and Metastasis - Therapeutic Strategies in Cancer Biology and Pathology - page 124

GPCR PKC RTK

GRK2

Raf1

RKIP P RKIP

Raf1

MEK

ERK/MAPK

Figure 22.1 GPCR and RTK mediation of ERK/MAPK signalling and the involvement of
RKIP in its regulation. Upon PKC-induced phosphorylation of serine-153, RKIP loses its
ability to inhibit Raf-1, but it can now inhibit GRK2 and influence GPCR and the interacting
EGF signalling pathways. This illustration is based on Lorenz et al. (2003), Kolch (2005) and
references discussed in the text.

Wnt GSK3-β degrades

Snail

RKIP

E-cadherin ? Notch/NICD

Epithelial mesenchymal transition

Figure 22.2 The potential interaction of Notch and Wnt signalling with RKIP function
mediated by Snail. Loss of RKIP is said to stabilise β-catenin and induce expression of other
markers such as c-met and vimentin. This is based on references cited in the text.

with Raf-1 and conversely ligand bound RKIP inhibits RKIP phosphorylation non-
competitively and also prevents RKIP binding to Raf-1 (Granovsky et al., 2009).
RKIP operates in three distinctive ways, by inhibiting Raf-MEK-ERK, GPCR
kinase and NF-κB signalling. It inhibits Raf kinase activation by binding to the
phosphorylated form of Raf-1 and prevents Raf-1 kinase mediated phosphoryla-
tion and activation of MEK and also dissociates the RAF/MEK complex and said to
competitively inhibit MEK phosphorylation (Rath et al., 2008; Yeung et al., 1999).
In its phosphorylated form, RKIP also inhibits GRK2 (GPCR kinase 2) which is
negatively regulates GPCRs. As shown in Figure 22.1 upon dissociation from Raf-
1, RKIP couples with GRK2 and inhibits its activity. This occurs by PKC mediated
phosphorylation of RKIP (Lorenz et al., 2003; see also Kolch, 2005). In this way,
GPCR and EGF signalling pathways can interact and cross talk.
The third route is one by which RKIP targets NF-κB signalling. NF-κB is a survival
pathway that is inhibited by RKIP. So the loss of the latter in cancers leads to pro-