Cell News 4/2014
10
Research news
The role of calcineurin during development:
parallels and differences between higher and lower eukaryotes.
Sascha Thewes
Institute for Biology – Microbiology; Department of Biology, Chemistry, Pharmacy;
Freie Universität Berlin; 14195 Berlin; Germany
Email:
Abstract
Calcium is one of the most important signalling molecules in
all eukaryotes. Ca
2+
signals play a role in a plethora of cellular
and developmental processes. One important target of Ca
2+
-sig-
nalling is the Ser/Thr-phosphatase calcineurin. Calcineurin has
been identified to be the target for immunosuppressive drugs
like cyclosporine A and FK506. Therefore research with calci-
neurin was focused for a long time on its role in the immune
system. However, in the last decade calcineurin has been shown
to be involved in many developmental processes, especially in
lower eukaryotes like fungi and social amoebae. In this article
I will discuss the parallels in the role of calcineurin during de-
velopment of higher and lower eukaryotes. I show that lower
eukaryotes are excellent model organisms to study the func-
tion of this phosphatase. I will also depict that more research
about calcineurin is needed to elucidate the role(s) of different
isoforms as well as the spatiotemporal function of the protein.
Introduction
Calcineurin (protein phosphatase 2B, PP2B) is a Ca
2+
/calmo-
dulin-dependent Ser/Thr-phosphatase. The holoenzyme is a
heterodimer composed of a catalytic (calcineurin A, CNA) and
a regulatory (calcineurin B, CNB) subunit and has been inves-
tigated in detail mainly in mammalian cells and in the yeast
Saccharomyces cerevisiae
(reviewed in (Rusnak and Mertz,
2000; Cyert, 2003)). The enzyme is activated by an increase of
the cytosolic Ca
2+
-concentration (Fig. 1). After a stimulus, Ca
2+
enters the cytosol from the extracellular space or from internal
Ca
2+
stores like the mitochondria, the endoplasmatic reticulum,
or (in lower eukaryotes) the vacuole. Increase in the cytosolic
Ca
2+
-concentration then activates the calcium-sensing protein
calmodulin, which in turn can activate in cooperation with the
regulatory CNB subunit the catalytic CNA subunit. The active
phosphatase dephosphorylates its target proteins at serine and
threonine residues. Calcineurin has been identified as the target
of immunosuppressive drugs. The most prominent drugs inhi-
biting calcineurin function are cyclosporine A (CsA) and tac-
rolimus (FK506), which are also widely used in transplantation
medicine (Siekierka and Sigal, 1992)(Fig. 1).
Beside in mammals and in
S. cerevisiae
calcineurin has also been
investigated in other non-mammalian vertebrates (Liberatore
and Yutzey, 2004; Gajewski
et al.
, 2006; Fukazawa
et al.
, 2009;
Lee
et al.
, 2013; Kujawski
et al.
, 2014), and lower eukaryotes like
filamentous fungi (Chen et al., 2010), social amoebae (Horn and
Gross, 1996; Weissenmayer et al., 2005; Boeckeler et al., 2006;
Thewes et al., 2014), various parasites and amoeboflagellates
(Remillard et al., 1995; Kumar et al., 2004; Moreno et al., 2007;
Araya et al., 2008; Naderer et al., 2011), and in
Paramecium
(Fraga et al., 2010). Additionally, many target proteins of this
phosphatase have been identified in different organisms (revie-
wed in (Li et al., 2011)), of which the best-investigated targets
are the orthologues of the mammalian transcription factor NFAT
(nuclear factor of activated T-cells) and the yeast transcription
factor Crz1, respectively (Thewes, 2014).
In this review I will focus on the direct involvement of calcineu-
rin in various developmental processes of higher and lower eu-
karyotes without discussing the role of calcineurin downstream
targets in detail. I will point out that many basic principles of
calcineurin-dependent developmental processes are conserved
between lower and higher eukaryotes therefore making lower
eukaryotes good models to study the fundamental function of
calcineurin during development.
