threshold might induce the phosphorylation of JAM-A. This phosphorylation will control the affinity for Afadin thereby controlling
the contraction of apical cytoskeleton that allows for the maintenance of ZA and TJs.
4.4 SCRIBBLE
SCRIBBLE is a classical multimodular scaffold protein that contains 16 leucine-rich repeats (LRR) and four PDZ domains.
N-terminal LRR domain can associate with LGL and is required
for the association with the lateral cortex and the establishment of
apicobasal polarity [97, 98]. The C-terminal PDZ domains of
SCRIBBLE can interact with a diverse range of proteins such as
β-Pix [99], Vangl2 [100], and LGN [101], allowing for cell polarization, cell migration [102], establishment of planar cell polarity,
and cell division, respectively. In epithelial cells, SCRIBBLE is
required for normal intercellular adhesion by stabilizing E-cadherin–p120 catenin at the plasma membrane [103]. 10 years ago,
E-cadherin complex was tagged as a mechanosensor complex. Since
then many studies using different approaches such as FRET sensor,
magnetic tweezer, and cell stretching have confirmed that
E-cadherin can sense changes in mechanical forces within an epithelial monolayer [104–106]. The role of SCRIBBLE in mechanotransduction has, however, not been investigated so far. Some
hints based on the function of SCRIBBLE in the stabilization of
E-cadherin point to a role in the mechanoregulation of AJs.
E-cadherin receptors form adhesive clusters that are coupled to
the contractile actomyosin cortex [107, 108]. At the cellular level,
E-cadherin adhesion not only binds cells together but also mechanically couples the contractile modules of neighboring cells together
to generate junctional tension [109]. This junctional tension has
been mainly treated as homogeneous along the cell–cell interface.
However, E-cadherin forms clusters of different sizes along the
junctions between cells [108–110]. Interestingly, despite overall
basolateral localization, SCRIBBLE is enriched at the ZAs, where
it stabilizes E-cadherin–p120 catenin adhesions [111, 112]. At the
level of the ZAs, clusters of stabilized E-cadherin are linked to large
actomyosin bundles [113–115]. Below the AJs, at the lateral adherens junctions (LAJs), E-cadherin is coupled to less aligned actomyosin network. Contractile tension is thereby greater at the ZA
than at the LAJ. SCRIBBLE could be enriched at the ZA in a
tension-dependent manner, and thereby by stabilizing E-cadherin
could be implicated in a feedback positive loop in the generation of
forces at the ZAs. This tension driven localization of SCRIBBLE to
E-cadherin can also take place during the orientation of the mitotic
spindle to align epithelial cell division. In 2017, Hart et al., by
applying uniaxial stretch on epithelial cells, showed that cell division
aligned with the stretch axis [116]. The orientation of this cell
division axis requires trans-engagement of E-cadherin adhesions
and involves tension-dependent recruitment of LGN to
Mechanoregulation of PDZ Proteins
267
the contraction of apical cytoskeleton that allows for the maintenance of ZA and TJs.
4.4 SCRIBBLE
SCRIBBLE is a classical multimodular scaffold protein that contains 16 leucine-rich repeats (LRR) and four PDZ domains.
N-terminal LRR domain can associate with LGL and is required
for the association with the lateral cortex and the establishment of
apicobasal polarity [97, 98]. The C-terminal PDZ domains of
SCRIBBLE can interact with a diverse range of proteins such as
β-Pix [99], Vangl2 [100], and LGN [101], allowing for cell polarization, cell migration [102], establishment of planar cell polarity,
and cell division, respectively. In epithelial cells, SCRIBBLE is
required for normal intercellular adhesion by stabilizing E-cadherin–p120 catenin at the plasma membrane [103]. 10 years ago,
E-cadherin complex was tagged as a mechanosensor complex. Since
then many studies using different approaches such as FRET sensor,
magnetic tweezer, and cell stretching have confirmed that
E-cadherin can sense changes in mechanical forces within an epithelial monolayer [104–106]. The role of SCRIBBLE in mechanotransduction has, however, not been investigated so far. Some
hints based on the function of SCRIBBLE in the stabilization of
E-cadherin point to a role in the mechanoregulation of AJs.
E-cadherin receptors form adhesive clusters that are coupled to
the contractile actomyosin cortex [107, 108]. At the cellular level,
E-cadherin adhesion not only binds cells together but also mechanically couples the contractile modules of neighboring cells together
to generate junctional tension [109]. This junctional tension has
been mainly treated as homogeneous along the cell–cell interface.
However, E-cadherin forms clusters of different sizes along the
junctions between cells [108–110]. Interestingly, despite overall
basolateral localization, SCRIBBLE is enriched at the ZAs, where
it stabilizes E-cadherin–p120 catenin adhesions [111, 112]. At the
level of the ZAs, clusters of stabilized E-cadherin are linked to large
actomyosin bundles [113–115]. Below the AJs, at the lateral adherens junctions (LAJs), E-cadherin is coupled to less aligned actomyosin network. Contractile tension is thereby greater at the ZA
than at the LAJ. SCRIBBLE could be enriched at the ZA in a
tension-dependent manner, and thereby by stabilizing E-cadherin
could be implicated in a feedback positive loop in the generation of
forces at the ZAs. This tension driven localization of SCRIBBLE to
E-cadherin can also take place during the orientation of the mitotic
spindle to align epithelial cell division. In 2017, Hart et al., by
applying uniaxial stretch on epithelial cells, showed that cell division
aligned with the stretch axis [116]. The orientation of this cell
division axis requires trans-engagement of E-cadherin adhesions
and involves tension-dependent recruitment of LGN to
Mechanoregulation of PDZ Proteins
267