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

49 imb researchers: molecular cell biology
ALPHA YAP
CADHERIN ADHESION AND TISSUE ORGANISATION
IN HEALTH AND DISEASE
actin cytoskeleton, thereby influencing cell
shape, adhesion, and cell-cell cohesion.
Relevant signals include the Rho family
GTPases and Src family kinases. These
affect a range of cytoskeletal regulators,
including actin nucleators, cross-linking
proteins, scaffolds and the myosins II and
VI. We aim to understand the dynamic
spatial and temporal regulation of the
cytoskeleton by cadherin signalling, with
a view to understanding how these key
elements are used during development
and tissue maintenance, and how they are
disrupted in human disease.
CELLS ARE THE BUILDING BLOCKS
of our bodies. Interactions between
different cells are important to shape
our developing bodies and maintain the
organisation of our tissues in health. A
range of diseases occur when those
interactions are disturbed, including
cancer and inflammation. My laboratory
studies one set of cell-to-cell interactions,
those that occur when cells attach to one
another. We focus on the cadherin family
of cell-cell adhesion receptors. These
critically determine the ability of cells
to recognise one another and organise
into coherent tissues. The importance of
these receptors is emphasised by the fact
that loss of cadherin function promotes
cancer progression in epithelial tissues
(such as the breast and colon) – the
commonest form of human cancers.
Cadherin dysfunction also contributes to
the breakdown of epithelial barriers during
inflammation, notably in chronic disease
of the intestine. By understanding the
basic biological mechanisms of cadherinmediated
cell recognition, we thus hope
to provide vital insights into the basis of
developmental patterning and common
human diseases.
Currently we focus on understanding
how cadherins cooperate with the actin
cytoskeleton, long believed to be central to
cadherin function. Our experience makes
it increasingly clear that this cooperation
involves a complex interplay between
adhesion receptors and diverse distinct
states of the cytoskeleton, coordinated
by a variety of signalling pathways at the
cell membrane. In particular, our work
demonstrates that cadherins function as
adhesion-activated cell signalling receptors
that stimulate pathways to regulate the
An important challenge we are beginning
to confront is how to understand the
complexity of cytoskeletal regulation
at cell-cell junctions. Our research
experience, accrued over the past several
years, indicates that multiple cytoskeletal
regulators are coordinated at cadherin
adhesion to control junctional dynamics,
homeostasis and integrity. How then do we
develop a coherent model to encompass
this complex system A significant
breakthrough is our recent discovery,
published in Nature Cell Biology (Smutny
et al., 2010), that these cell signals and
effectors function in modules, where key
effectors are subject to specific signal
regulation and have distinct cellular
functions, that synergise to support
junction integrity. This work was the subject
of an editorial review in Nature Cell Biology
and highlighted on Faculty of 1000. We
are now working with Dr Nick Hamilton to
develop mathematical tools to measure
and model these complex systems.
RESEARCH PROJECTS
• Regulation of the actin cytoskeleton by
E-cadherin
• Cooperation between cadherins and
myosin motors at cell-cell contacts
• Cooperativity between cadherins and
microtubules
• Cadherin signalling to Src family kinases:
defining the pathway(s)
• The morphogenetic consequences of
cadherin-activated cell signalling and
cooperativity with the actin cytoskeleton
KEY PUBLICATIONS
Smutny, M., Cox, H.L., Leerberg, J.,
Kovacs, E.M., Conti, M.A., Ferguson, C.,
Hamilton, N.A., Parton, R.G., Adelstein,
R.S., and Yap, A.S. (2010). Myosin
II isoforms identify distinct functional
modules that support integrity of the
epithelial zonula adherens. Nature Cell
Biology 12: 696-702.
Den Elzen, N., Buttery, C.V., Maddugoda * ,
M.P., Ren * , G., and Yap, A.S. (2009).
Cadherin adhesion receptors orient the
mitotic spindle during symmetric cell
division in mammalian epithelia. Molecular
Biology of the Cell 20: 3740-3750. ( * Equal
contributions)
Ren, G * ., Helwani * , F.M., Verma * , S.,
McLachlan, R.W., Weed, S.A., and Yap,
A.S. (2009). Cortactin is a functional target
of E-cadherin-activated Src family kinases
in MCF-7 epithelial monolayers. Journal
of Biological Chemistry 284: 18913-
18922. ( * Equal contributions)
Akhmanova, A. and Yap, A.S. (2008).
Organizing junctions at the cell-cell
interface. Cell 135: 791-793.
LAB MEMBERS
Senior Research Officer: Dr Eva Kovacs
Research Officers: Dr Guillermo
Gomez, Dr Michael Smutny, Dr Aparna
Ratheesh, Dr Robert McLachlan, Dr Karen
Chambers, Dr Siew Ping Han
Research Assistants: Suzie Verma, Kris
Blucher
PhD Students: Sabine Mangold, Joanne
Leerberg, Vincent Leong, Selwin Wu