Download EPH-ective control of cytokinesis

CELL CYCLE
2016, VOL. 0, NO. 0, 1–2
http://dx.doi.org/10.1080/15384101.2016.1251230
EDITORIALS: CELL CYCLE FEATURES
EPH-ective control of cytokinesis
Thomas Jungasa, Arnaud Besson
b,c
, and Alice Davya
Centre de Biologie du Developpement (CBD), Centre de Biologie Integrative (CBI), Universite de Toulouse, CNRS, UPS, Toulouse, France;
INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France; cCNRS ERL5294, Universite de Toulouse, UPS, Toulouse, France
a
b
ARTICLE HISTORY Received 14 October 2016; Accepted 17 October 2016
KEYWORDS abscission; cancer; cell division; citron kinase; ephrin; mouse; multicellularity; neural progenitors; polyploid neurons
Experimental evidence in the unicellular choanoflagellate
Salpingoeca rosetta, the closest living relative of animals,
proposes that emergence of multicellularity – one of the founding step of animal life – is caused by incomplete separation of
daughter cells at the last step of cell division, cytokinesis.1
Incomplete cytokinesis also occurs in animals, giving rise to
polyploid cells (hepatocytes) or syncitia (germ cells). Until
recently cytokinesis was viewed as a mechanism orchestrated
only by cell intrinsic factors,2 yet in Salpingoeca Rosetta the
switch from unicellular to multicellular state can be driven by
extrinsic factors such as predators, changes in ocean chemistry
or emergence of new ecological niches.1 These observations
indicate that completion of cytokinesis may be controlled by
factors present in the environment of dividing cells.
In our recent study,3 we asked whether cytokinesis is similarly controlled by extracellular cues in mammals, focusing on
the role of local communication via Eph/ephrin signaling. Eph
receptor tyrosine kinases and their membrane-bound ligands,
ephrins, are best known for their role in modulating cell
adhesion and migration, mostly through the regulation of the
actin cytoskeleton.4 Using live and fixed cell microscopy, we
observed in various cell lines that activation of the EphB2
receptor induced cytokinesis delays and/or failures, which correlated with an increased number of polyploid cells. We showed
that EphB2 tyrosine kinase activity was necessary for cytokinesis defects and we identified Citron kinase (CitK) as a downstream target of EphB2 signaling. CitK is a serine/threonine
kinase that plays a well characterized function in cytokinesis.5
We found that CitK interacts with EphB2; that it is phosphorylated on tyrosine upon activation of Eph signaling and that this
phosphorylation is mediated by Src. Using Mass Spectrometry
we identified 2 tyrosine residues located in the Rho Binding
domain of CitK that are phosphorylated by Src. Functional
assays with engineered phosphomimetic and unphosphorylatable mutants of CitK confirmed that phosphorylation of these
residues modulates CitK interaction with RhoA and alters
cytokinesis.
To demonstrate the physiological relevance of these
in vitro observations, we focused on dividing neural progenitors (NPs) of the neocortex since Eph receptors and
ephrins are expressed in these cells and CitK has been
shown in mouse, rat and humans to play a critical role in
NP cytokinesis.6 We showed that CitK and EphB2 partially
co-localize in dividing NPs in vivo and that CitK is phosphorylated on tyrosine in these cells. More importantly, we
found that pups lacking EphB2 signaling exhibit a decrease
in the fraction of polyploid cortical neurons which we used
as a read-out of NP cytokinesis failure.3
Thus, our study reports for the first time a complete molecular cascade downstream of Eph signaling controling cytokinesis. Interestingly, all the actors of this cascade are present in the
genome of Salpingoeca rosetta: Eph receptors, Src kinase and a
citron kinase-like protein.1,7 In addition, our study confirms
that cytokinesis can be controlled by cues present in the
environment of dividing cells in mammals and suggests that
CitK plays a key role in the completion of cytokinesis as an
integrator of both intrinsic and extrinsic information.
Our findings raise a number of questions (Fig. 1), first with
respect to the role of Eph/ephrin signaling in cancer. Indeed,
Eph signaling deregulation is observed in many cancers, but
until now its role was restricted to metastatic diffusion and
tumor aggressiveness. Our data showing that Eph-induced
cytokinesis failure leads to aneuploidy, suggests that Eph/ephrin signaling may play a role in cancer initiation by promoting
genetic instability.
More puzzling questions raised by our study concern the
observation that Eph/ephrin signaling controls neuronal polyploidy. In mammals, the majority of cells are diploid except for
a handful of cell types (gametes, hepatocytes and cardiomyocytes). The existence of polyploid neurons in mammals was
reported several years ago, yet little is known about these neurons. Is there an advantage for neurons in being polyploid?
Is polyploidy an additional source of neuronal diversity and
does it participate in the complexity of the mammalian brain?
What is the significance of its regulation by local signaling via
Eph/ephrin?
In conclusion, modulation of cytokinesis by environmental
information appears as an important mechanism driving evolution, from emergence of multicellularity to generation of neuronal diversity.
CONTACT Alice Davy
[email protected]
Center for Integrative Biology (CBI), 118 route de Narbonne, Toulouse, France
Feature to: Jungas T, et al. Eph-mediated tyrosine phosphorylation of citron kinase controls abscission. J Cell Biol 2016; 214(5):555-69; PMID: 27551053; http://dx.doi.org/
10.1083/jcb.201602057.
© 2016 Taylor & Francis
2
T. JUNGAS ET AL.
Figure 1. An Eph-induced signaling cascade prevents cytokinesis completion: possible physiological and pathological consequences. Activation of Eph signaling in
dividing cells interrupts or delays cytokinesis which increases the fraction of polyploid cells. In the neocortex polyploid neurons could participate in generating neuronal
diversity while in other tissues, cytokinesis defects could increase genomic instability and participate in tumor initiation.
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
[4]
ORCID
[5]
Arnaud Besson
http://orcid.org/0000-0002-9599-3943
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