Visit our Expo - Redox and Inflammation signaling 2012

THE NDR KINASE FAMILY: REGULATORS OF CELL PROLIFERATION AND
MORPHOGENESIS
Hemmings, B.A., Hergovich, A., Schmitz, D., Kohler, R., Vichalkovski, A., Cornils, H.,
Stegert, M.R., Tamaskovic, R., and Bichsel, S.J.
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
The NDR (nuclear-Dbf2-related) family of proteins is a group of serine/threonine kinases
conserved from yeast to mammals which are important regulators of cell morphogenesis and
proliferation. They are members of AGC kinases (protein kinases A, G, and C) and include
the following protein kinases NDR, LATS, Cbk1, Orb6, Cot-1 and Dbf2. Although, the
precise function(s) of the mammalian NDR kinases still needs to be defined, evidence
suggests that NDR might be involved in tumor progression. NDR1 is hyper-activated in
several S100B-positive melanoma cell lines, and thus given that S100B is over expressed in
more than 80% of metastatic melanomas, NDR1 could potentially influence tumor metastasis
potential. Moreover, disruption of the murine NDR2 gene by insertional mutagenesis was
found to result in B-cell lymphomas, suggesting that both mammalian forms of NDR kinase
might be involved in tumor initiation or progression.
Interestingly, in Saccharomyces cerevisiae, the NDR relative Dbf2 constitutes an integral part
of mitotic exit network (MEN), whereas the other NDR homologue in budding yeast, Cbk1, is
required for regulating morphological changes (RAM network). Recent genetic studies of
yeast have unraveled many key players in processes regulating these NDR-related proteins.
Importantly, these studies demonstrated that the budding yeast relatives of human NDR,
interact with Mob1 (Mps one binder 1) and Mob2, respectively. A crucial interaction required
for the activity and biological functions of these yeast kinases.
Recent work from our laboratory has shown human NDR1 and NDR2 to be regulated in a
similar fashion. Both proteins are efficiently activated upon treatment of cells with the protein
phosphatase 2A inhibitor, okadaic acid (OA). Upon activation, phosphorylation occurs on the
activation segment site, Ser281 (Ser282 for NDR2), and the hydrophobic motif site, Thr444
(Thr442 for NDR2). Phosphorylation of Ser281 occurs by autophosphorylation, whereas
Thr444 is targeted by an upstream kinase, recently identified as the Ste20-like kinase MST3.
Significantly, phosphorylation of both sites is crucial for NDR activity in vitro and in vivo.
Further, we found evidence that human MOB1 (hMOB1), the closest relative of yeast Mob1
and Mob2, stimulates NDR kinase activity and interacts with NDR both in vivo and in vitro.
hMOB1 activates NDR1 at the membrane and membrane association of NDR1 was dependent
on the domain required for hMOB1 binding.
Recent developments regarding the regulation and function of this emerging signaling
pathway will be presented.
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