forces, but only few examples are known so far. In epithelial cells,
the adhesion machineries at the cell–cell or cell–substrate interfaces
are known to play an important role in mechanotransduction
[10, 19]. These machineries are composed of several proteins,
and many of them are part of the PDZ family [20]. Being
integrated in a complex modular array tethering the cell membrane
to the cell cytoskeleton, the adhesion scaffolding PDZ proteins
might constitute an important link to transduce the mechanical
signals into an appropriate cell response to maintain cellular
homeostasis. We will thus focus on PDZ proteins from the adhesion machinery that have been recently shown to be regulated by
forces in a direct or indirect manner (Fig. 1).
3 Force Regulated PDZ Proteins
3.1 ZO1
ZO1 is a tight junction scaffolding protein that belongs to the
MAGUK (membrane associated guanylated kinase homolog) family. It is characterized by the occurrence of three PDZ, one SH3 and
a GUK (guanylate kinase homologous domain) domains
[21]. ZO1 is a cytoplasmic protein, that anchors actin filaments
through its actin binding domain at its C terminal region
[22, 23]. At the N-terminus, the PDZ1 and PDZ3 domains bind
to the tight junction membrane associated proteins, Claudins and
JAM-A, and to TAZ, a member of Hippo pathway, while the PDZ2
domain promotes heterodimerization between ZO1 and either
ZO2 or ZO3 [22, 24–26]. A larger region encompassing the
PDZ3, SH3, U5, and GUK domains (ZPSG-1) interacts with and
recruits to junctions the transmembrane TJ protein occludin, but
also DbpA/ZONAB (DNA binding protein A/ZO1 associated
Nucleic Acid-binding protein) [27, 28]. The sequestration of
DbpA by ZO1 and ZO2 at the junctions of confluent monolayers
inhibits its nuclear activity that regulates gene expression and cell
proliferation [27–30].
Recently, Spadaro et al. demonstrated that ZO1 stretches upon
mechanical forces [31]. In 2011, Then et al. have already proposed
an impact of membrane tension on the localization of ZO1
[32]. Under hyperosmotic stress that generates an increase in
membrane tension, the actin cytoskeleton is reorganized with the
appearance of a dense F-actin cortical ring. In this condition, ZO1
expression is increased, and it colocalizes with the newly formed
actin ring [32]. As ZO1 is anchored to the actin filaments through
its C-terminal region, this change in actin organization exerts direct
pulling forces on the ZO1 protein. When present as a heterodimer
with ZO2 within cells, ZO1 is in a stretched configuration that
allows binding to DpbA. However, the depletion of ZO2 together
with an inhibition of myosin contractility promotes a folding of the
N-terminal and C-terminal end of ZO-1, and releases the
Mechanoregulation of PDZ Proteins
259
the adhesion machineries at the cell–cell or cell–substrate interfaces
are known to play an important role in mechanotransduction
[10, 19]. These machineries are composed of several proteins,
and many of them are part of the PDZ family [20]. Being
integrated in a complex modular array tethering the cell membrane
to the cell cytoskeleton, the adhesion scaffolding PDZ proteins
might constitute an important link to transduce the mechanical
signals into an appropriate cell response to maintain cellular
homeostasis. We will thus focus on PDZ proteins from the adhesion machinery that have been recently shown to be regulated by
forces in a direct or indirect manner (Fig. 1).
3 Force Regulated PDZ Proteins
3.1 ZO1
ZO1 is a tight junction scaffolding protein that belongs to the
MAGUK (membrane associated guanylated kinase homolog) family. It is characterized by the occurrence of three PDZ, one SH3 and
a GUK (guanylate kinase homologous domain) domains
[21]. ZO1 is a cytoplasmic protein, that anchors actin filaments
through its actin binding domain at its C terminal region
[22, 23]. At the N-terminus, the PDZ1 and PDZ3 domains bind
to the tight junction membrane associated proteins, Claudins and
JAM-A, and to TAZ, a member of Hippo pathway, while the PDZ2
domain promotes heterodimerization between ZO1 and either
ZO2 or ZO3 [22, 24–26]. A larger region encompassing the
PDZ3, SH3, U5, and GUK domains (ZPSG-1) interacts with and
recruits to junctions the transmembrane TJ protein occludin, but
also DbpA/ZONAB (DNA binding protein A/ZO1 associated
Nucleic Acid-binding protein) [27, 28]. The sequestration of
DbpA by ZO1 and ZO2 at the junctions of confluent monolayers
inhibits its nuclear activity that regulates gene expression and cell
proliferation [27–30].
Recently, Spadaro et al. demonstrated that ZO1 stretches upon
mechanical forces [31]. In 2011, Then et al. have already proposed
an impact of membrane tension on the localization of ZO1
[32]. Under hyperosmotic stress that generates an increase in
membrane tension, the actin cytoskeleton is reorganized with the
appearance of a dense F-actin cortical ring. In this condition, ZO1
expression is increased, and it colocalizes with the newly formed
actin ring [32]. As ZO1 is anchored to the actin filaments through
its C-terminal region, this change in actin organization exerts direct
pulling forces on the ZO1 protein. When present as a heterodimer
with ZO2 within cells, ZO1 is in a stretched configuration that
allows binding to DpbA. However, the depletion of ZO2 together
with an inhibition of myosin contractility promotes a folding of the
N-terminal and C-terminal end of ZO-1, and releases the
Mechanoregulation of PDZ Proteins
259