demonstrated to recruit or organize other proteins at the plasma
membrane to coordinate signal transduction pathways within the
cytoplasm and nucleus [71]. A study done in 2016, using a cell
mechanical stretch device shows that CASK expression and localization to the basal membrane is needed for the inhibition of
proliferation of cells under cyclic stretch [72]. The authors show
that CASK interacts with ß1-integrin, however, the tension-driven
interaction between these two proteins still has to be formally
proven. Depletion of CASK results in aberrant proliferation of
cells under mechanical stress demonstrating that CASK localization
under tension is important for the mechanoregulation of the cell
division [72]. In 2019, Porter et al. demonstrated that the direct
interaction of CASK with DLG is required for normal cortical
recruitment of NUMA, a key component of spindle orientation
machinery [73]. Disruption of this interaction affects the integrity
of epithelial architecture and results in misoriented cell division that
give rise to multilumen cyst in 3D. Since the formation of 3D cysts
generates an increase in tension at the cell–cell interface [74], it is
tempting to speculate that CASK is recruited at the cell–cell interface in a force-dependent manner and then will recruit DLG allowing the formation of well polarized 3D cysts.
DLG interacts with the C terminal PDZ binding domain of
CD97 and together these proteins are part of the adherens junctional signaling complex composed of E-cadherin and catenins
[75]. This macromolecular complex is linked to the F actin cortex
and is thus submitted to cellular forces. The localization of CD97 at
the plasma membrane is actin dependent as blocking actin polymerization and elongation prevents its membrane localization. When
present at the cell membrane CD97 strengthens the adherens
junction (AJs) [76] while deletion of its PDZ binding domain
results in the loss of cell–cell contacts [77] upon mechanical shear
stress. Taken together these data show a role of CD97 in the
mechanoregulation of cell–cell contacts. In a recent study, mechanical stimulation of epithelial cells applied by using shear stress or
wound assay results in a rapid phosphorylation of Ser740 of CD97.
This phosphorylation disrupts the binding of DLG1 to the PDZ
binding domain of CD97, and correlates with a disorganization of
the actin cytoskeleton. PKC contributes to the mechanical force
induced cellular responses [78] and is a potential candidate to
phosphorylate CD97 at S740. PKCα interacts via its PBM with
PDZ3 domain of DLG1 [79]. Upon mechanical stress, PKCα
might be recruited to the cell membrane via DLG1 and will then
trigger phosphorylation of CD97 causing F-actin depolymerization, loss of cell–cell contact, and DLG1 detachment. This signaling pathway when activated induces depolymerization of actin and
loss of cell–cell contacts, that will result in a relaxation of the
tension at this particular cellular junction avoiding tissue breaking.
Mechanoregulation of PDZ Proteins
265
membrane to coordinate signal transduction pathways within the
cytoplasm and nucleus [71]. A study done in 2016, using a cell
mechanical stretch device shows that CASK expression and localization to the basal membrane is needed for the inhibition of
proliferation of cells under cyclic stretch [72]. The authors show
that CASK interacts with ß1-integrin, however, the tension-driven
interaction between these two proteins still has to be formally
proven. Depletion of CASK results in aberrant proliferation of
cells under mechanical stress demonstrating that CASK localization
under tension is important for the mechanoregulation of the cell
division [72]. In 2019, Porter et al. demonstrated that the direct
interaction of CASK with DLG is required for normal cortical
recruitment of NUMA, a key component of spindle orientation
machinery [73]. Disruption of this interaction affects the integrity
of epithelial architecture and results in misoriented cell division that
give rise to multilumen cyst in 3D. Since the formation of 3D cysts
generates an increase in tension at the cell–cell interface [74], it is
tempting to speculate that CASK is recruited at the cell–cell interface in a force-dependent manner and then will recruit DLG allowing the formation of well polarized 3D cysts.
DLG interacts with the C terminal PDZ binding domain of
CD97 and together these proteins are part of the adherens junctional signaling complex composed of E-cadherin and catenins
[75]. This macromolecular complex is linked to the F actin cortex
and is thus submitted to cellular forces. The localization of CD97 at
the plasma membrane is actin dependent as blocking actin polymerization and elongation prevents its membrane localization. When
present at the cell membrane CD97 strengthens the adherens
junction (AJs) [76] while deletion of its PDZ binding domain
results in the loss of cell–cell contacts [77] upon mechanical shear
stress. Taken together these data show a role of CD97 in the
mechanoregulation of cell–cell contacts. In a recent study, mechanical stimulation of epithelial cells applied by using shear stress or
wound assay results in a rapid phosphorylation of Ser740 of CD97.
This phosphorylation disrupts the binding of DLG1 to the PDZ
binding domain of CD97, and correlates with a disorganization of
the actin cytoskeleton. PKC contributes to the mechanical force
induced cellular responses [78] and is a potential candidate to
phosphorylate CD97 at S740. PKCα interacts via its PBM with
PDZ3 domain of DLG1 [79]. Upon mechanical stress, PKCα
might be recruited to the cell membrane via DLG1 and will then
trigger phosphorylation of CD97 causing F-actin depolymerization, loss of cell–cell contact, and DLG1 detachment. This signaling pathway when activated induces depolymerization of actin and
loss of cell–cell contacts, that will result in a relaxation of the
tension at this particular cellular junction avoiding tissue breaking.
Mechanoregulation of PDZ Proteins
265