Cell News 4/2014
17
Function of mammalian cell polarity regulators
in skin cancer
Melina Mescher and Sandra Iden*, PhD
Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases (CECAD),
and Center for Molecular Medicine Cologne (CMMC)
CECAD Research Center at the University of Cologne
Joseph-Stelzmann-Str. 26 | 50931 Cologne, Germany |
*: corresponding author: Phone: +49 221 478 89587 | e-mail:
Abstract
Establishment of cell polarity and orchestrated tissue architec-
ture are critical to development, organ homeostasis and rege-
neration. Almost every cell type in our body at least transiently
polarizes based on intrinsic cues or upon extrinsic stimuli, the-
reby contributing to various organismal functions. Alterations in
adhesion, polarity and architecture of tumor cells are hallmarks
of cancer and implicated in tumor growth, invasion and me-
tastasis. Seminal work in Drosophila and mammalian cell cul-
ture suggested a molecular connection between regulation of
polarity and oncogenic processes. Recent advance stems from
different mouse models that revealed a causal link between
polarity protein dysfunction and the formation and progression
of cancer. The Iden laboratory investigates the
in vivo
role of
mammalian polarity proteins in cell and tissue polarity, tissue
homeostasis and pathologic conditions such as cancer (Iden
and Collard 2008; Iden et al. 2012a; Ellenbroek et al. 2012).
We assess how polarity proteins including the Par3/aPKC com-
plex regulate growth and survival, cytoskeletal rearrangement,
fate decisions and differentiation, and how dysfunction of these
proteins affects oncogenic processes. In this focus article we
concentrate on recent insight into the role of epidermal Par3
in formation and progression of different types of skin cancer.
Molecular control of cell polarity
Cell polarity refers to the unequal distribution of macromolecu-
les like RNA, proteins and lipids, or to the specific positioning
of entire cellular compartments and organelles within a cell to
produce asymmetry in structure and function. Establishment
and maintenance of polarity regulate a wide range of cell beha-
viors (Iden and Collard, 2008; Macara and Mili, 2008; Niessen et
al., 2012; Simons and Mlodzik, 2008; St Johnston and Ahringer,
2010). Research of the past two decades unraveled a variety of
molecular regulators of cell polarity that contribute to processes
like directed cell migration, apico-basal polarity, oriented cell
divisions, cell fate determination or directed vesicular transport.
Polarity proteins couple control of cell shape to crucial signaling
pathways regulating growth and survival, metabolism, cell fate
and differentiation. Most of these regulators are evolutionary
conserved, and studies in animal model organisms including fly,
nematodes, zebrafish, frog and mice identified common but also
unique functions in polarization processes of multicellular or-
ganisms.
In a genetic screen for mutants affecting the first asymmetric
division of C.elegans embryos, Kenneth Kemphues and colle-
agues (1988) identified six partitioning-defective genes, Par-1
to Par-6, as critical players in this process. Specific localization
and function of individual Par proteins is required for asymme-
tric segregation of cytoplasmic and cortical factors (Kemphues
2000). In mammalian epithelia, these proteins localize to di-
stinct sites at intercellular adhesions or in the cytoplasm. The
activation of the Ser/Thr kinases Par1, Par4 and aPKC and sub-
sequent phosphorylation of polarity proteins define Par protein
localization and interaction with other proteins (fig. 1A). Based
on their physical or genetic interactions polarity proteins are
grouped into three classical polarity protein complexes, the api-
cal Par3-aPKC–Par6 complex, and Crumbs-Stardust/Pals1-PATJ
as well as Scribble-Discs Large(Dlg)-Lethal Giant Larvae (Lgl),
which have been discovered in Drosophila (Knust 1994; Bilder
2004) (fig. 1A). However, individual components of all three
complexes can interact with each other. Owing to their recently
acknowledged role in regulation of cell polarity, a group of “no-
vel” polarity proteins including Yurt, Coracle, Neurexin and Na+/
K+ ATPase has been added to the list of polarity proteins (Tepass
2012).
The Par3 complex has the most ubiquitous function, and is in-
volved e.g. in apico-basal polarity, asymmetric cell division and
polarization of neuronal and T cells (Macara, 2004). Par3, aPKC
and Par6 can form a ternary complex, but in certain processes
Par3 is excluded from the aPKC-Par6 domain through aPKC-
mediated phosphorylation (Morais-de-Sa et al., 2010; Horikoshi
et al., 2009)(fig. 1A). Par3 binds multiple proteins including the
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