reorganization of the actin cytoskeleton as mentioned previously
but also through differential expression of proteins, that move to
the junctions to counterbalance the changes in membrane tension.
Depletion of MUPP1, results in a disruption of the TJ barrier, with
a drop of transepithelial resistance of about 25% [42]. Molecularly,
depletion of MUPP1, in hyperosmotic conditions, triggers a
decreased expression and loss of membrane localization of Claudin4, a TJ protein [42]. These data clearly show that MUPP1 is
important in the maintenance of the epithelial homeostasis and
confirm previous study that pointed out a predominant role of
MUPP1 in the disruption of both TJs barrier and apicobasal polarity [43–45]. A more recent study shows that MUPP1 stability and
degradation in endothelial cells depends on the regulation of
PDZRN3, an E3 ubiquitin ligase PDZ domain containing ring
finger 3 protein [46]. The interactions between PDZRN3,
MUPP1, PAR3, and aPKC regulate the stabilization of TJs in
endothelial cells. Perturbation of PDZRN3 expression induces
degradation of MUPP1 that correlates with destabilization of the
actin cytoskeleton and disruption of the TJs. All these studies point
toward a role of MUPP1 in the stabilization and maintenance of
actin cytoskeleton and TJs in cells.
20 years ago, it was suggested that MUPP1 could change its
conformation through the interaction of its PDZ10 domain with
the 5-hydroxytryptamine type 2C receptors [47]. This interaction
induces a conformational change in MUPP1 and triggers a clustering of the 5-hydroxytryptamine type 2C receptors at the cell membrane, triggering downstream signal transduction pathways. It is of
interest that different PDZ domains of MUPP1 can bind to
CADM1, a transmembrane cell adhesion protein, with different
affinities. The PDZ2 of MUPP1, for example, presents the highest
affinity for CADM1, but when this PDZ is absent, CADM1 can still
interact with other PDZ domains of MUPP1. These data could
point to a change in conformation of MUPP1 that would unmask
the PDZ2 domain leading to a strong binding to CADM1
[48, 49]. In the case of CADM1 and maybe of other interactors
of MUPP1, the interactions with multiple domains can be an
alternative when some domains are either occupied by other ligands
or hidden by an autoinhibitory conformation of MUPP1. These
multi–low-affinity interactions might then serve as transient interaction contacts before MUPP1 reaches its stretched configuration.
However, the unfolding/folding regulation of MUPP1 is still
under debate as only indirect evidence has been obtained to date.
3.3 PAR3
PAR3 is part of the Partitioning defective proteins and presents a
CR1 oligomerization domain, 3 PDZ domains and aPKC binding
domain. A recent study pointed out that cortical forces are responsible for the clustering of PAR3 on the cell cortex. In C. elegans,
inhibition of actin contraction with blebbistatin or actin filament
262
Elsa Bazellie ` res and Andre ´ Le Bivic
but also through differential expression of proteins, that move to
the junctions to counterbalance the changes in membrane tension.
Depletion of MUPP1, results in a disruption of the TJ barrier, with
a drop of transepithelial resistance of about 25% [42]. Molecularly,
depletion of MUPP1, in hyperosmotic conditions, triggers a
decreased expression and loss of membrane localization of Claudin4, a TJ protein [42]. These data clearly show that MUPP1 is
important in the maintenance of the epithelial homeostasis and
confirm previous study that pointed out a predominant role of
MUPP1 in the disruption of both TJs barrier and apicobasal polarity [43–45]. A more recent study shows that MUPP1 stability and
degradation in endothelial cells depends on the regulation of
PDZRN3, an E3 ubiquitin ligase PDZ domain containing ring
finger 3 protein [46]. The interactions between PDZRN3,
MUPP1, PAR3, and aPKC regulate the stabilization of TJs in
endothelial cells. Perturbation of PDZRN3 expression induces
degradation of MUPP1 that correlates with destabilization of the
actin cytoskeleton and disruption of the TJs. All these studies point
toward a role of MUPP1 in the stabilization and maintenance of
actin cytoskeleton and TJs in cells.
20 years ago, it was suggested that MUPP1 could change its
conformation through the interaction of its PDZ10 domain with
the 5-hydroxytryptamine type 2C receptors [47]. This interaction
induces a conformational change in MUPP1 and triggers a clustering of the 5-hydroxytryptamine type 2C receptors at the cell membrane, triggering downstream signal transduction pathways. It is of
interest that different PDZ domains of MUPP1 can bind to
CADM1, a transmembrane cell adhesion protein, with different
affinities. The PDZ2 of MUPP1, for example, presents the highest
affinity for CADM1, but when this PDZ is absent, CADM1 can still
interact with other PDZ domains of MUPP1. These data could
point to a change in conformation of MUPP1 that would unmask
the PDZ2 domain leading to a strong binding to CADM1
[48, 49]. In the case of CADM1 and maybe of other interactors
of MUPP1, the interactions with multiple domains can be an
alternative when some domains are either occupied by other ligands
or hidden by an autoinhibitory conformation of MUPP1. These
multi–low-affinity interactions might then serve as transient interaction contacts before MUPP1 reaches its stretched configuration.
However, the unfolding/folding regulation of MUPP1 is still
under debate as only indirect evidence has been obtained to date.
3.3 PAR3
PAR3 is part of the Partitioning defective proteins and presents a
CR1 oligomerization domain, 3 PDZ domains and aPKC binding
domain. A recent study pointed out that cortical forces are responsible for the clustering of PAR3 on the cell cortex. In C. elegans,
inhibition of actin contraction with blebbistatin or actin filament
262
Elsa Bazellie ` res and Andre ´ Le Bivic