2010 Annual Report - Institute for Molecular Bioscience - University ...

imb annual report 2010
48
MIKE WATERS
ROLE OF GROWTH HORMONE AND RELATED
CYTOKINES IN GROWTH, CANCER, DIABETES
AND OBESITY
ADULT HEIGHT IS DETERMINED BY
the actions of growth hormone (GH) during
childhood and adolescence. In the adult,
growth hormone is an important metabolic
agent regulating body composition,
opposing the actions of insulin. In old
age, growth hormone status determines
lifespan, at least in animal models. We
study the means used by growth hormone
to achieve these changes, using a variety
of approaches directed to the growth
hormone receptor, from high-resolution
protein structures to genetically-engineered
animals.
The growth hormone receptor determines
the degree of the cell response to growth
hormone, which we originally cloned
collaboratively with Genentech. Through
FRET, BRET, crystallography and targeted
mutagenesis we have developed a new
model of how the GH receptor is activated
by GH, involving realignment of receptor
subunits within a constitutive dimer. An
extension of this model describes how a
rearrangement of an extracellular b-loop
of the GH receptor selectively controls
ERK activation without influencing Stat5
activation through the use of an alternate:
Src kinase.
By creating targeted knock-in mutations to
signalling domains within the GH receptor
cytoplasmic domain, we have shown that
enhancement of postnatal somatic growth
by GH is dependent on its ability to activate
the transcription factor Stat5. Because
these mice become strikingly obese
after 6 months of age, we are currently
investigating the role of Stat5a/b in control
of lipid and carbohydrate metabolism using
tissue-targeted gene deletion of Stat5a/b.
We have found that insulin secretion and
action are altered in these mice, and
their livers are grossly steatotic. We are
identifying the molecular targets of GH that
regulate these changes, using in vivo Cre
deletion of key transcription factors.
The surprising finding that the growth
hormone receptor is located in the cell
nucleus of dividing cells has led us to
discover that nuclear localised receptor
induces the expression of a key stem cell
marker. Because we have shown that GH
promotes neural stem cell proliferation, we
are studying the mechanism of this direct
gene induction by the GH receptor.
The absolute requirement for GH in liver
regeneration has led us to use our panel of
GH receptor signalling mutants to find the
identity of the regeneration signal.
RESEARCH PROJECTS
• Investigating the mechanism of
activation of growth hormone and
related cytokine receptors, including
the mechanism of activation of the
Src kinase constitutively bound to the
receptor
• Elucidating the role of the growth
hormone receptor in the cell nucleus
in relation to proliferation, oncogenesis
and stem cell proliferation
• Determining the role of GH-dependent
Stats 5/3/1 in lipid and carbohydrate
metabolism, including insulin action
• Establishing the molecular basis for
GH-dependent liver regeneration
• Establishing the molecular mechanism
underlying the long-term activation of
neural stem cells by GH
KEY PUBLICATIONS
Blackmore, D.G., Golmohammadi, M.G.,
Large, B., Waters, M.J., and Rietze, R.L.
(2009). Exercise increases neural stem cell
number in a growth hormone-dependent
manner, augmenting the regenerative
response in aged mice. Stem Cells 27:
2044-2052.
Conway-Campbell, B.L., Brooks, A.J.,
Robinson, P.J., Perani, M., and Waters,
M.J. (2008). The extracellular domain of
the growth hormone receptor interacts
with coactivator activator to promote cell
proliferation. Molecular Endocrinology 22:
2190-2202.
Lichanska, A.M., and Waters, M.J. (2008).
How growth hormone controls growth,
obesity and sexual dimorphism. Trends in
Genetics 24: 41-47.
Rowlinson, S.W., Yoshizato, H., Barclay,
J.L., Brooks, A.J., Behncken, S.N., Kerr,
L.M., Millard, K., Palethorpe, K., Nielsen,
K., Clyde-Smith, J., Hancock, J.F., and
Waters, M.J. (2008). An agonist-induced
conformational change in the growth
hormone receptor determines the choice
of signalling pathway. Nature Cell Biology
10: 740-747.
Schirra, H.J., Anderson, C.G., Wilson,
W.J., Kerr, L., Craik, D.J., Waters,
M.J., and Lichanska, A.M. (2008).
Altered metabolism of growth hormone
receptor mutant mice: a combined NMR
metabonomics and microarray study.
PLoS ONE 3: e2764.
LAB MEMBERS
Research Officers: Dr Andrew Brooks, Dr
Tim McPhee
Research Assistants: Kathryn Tunny,
Tania Brooks
PhD Students: Caroline Nelson, Yash
Chhabra
Masters Student: Qiushi Chen
Occupational Trainee: Morgane Roussel
Human melanoma line infected with mKATE2
expressing chicken virus, demonstrating ability
to deliver STAT5 dominant negative to halt
metastasis.