4.1 PAR6
PAR6 is part of the Partitioning defective proteins in C. elegans, and
encodes a protein with PKC binding domain (PB1), a semiCdc42/Rac1 interactive binding (CRIB) and a PDZ domain
[57]. Recently a PDZ binding motif (PBM) was identified at its
C-terminal region [58]. PAR6 in many species is involved in cell
division, cell polarization, and cell migration, processes that are
characterized by changes in cellular forces [59–61].
PAR6 function is able to segregate to the apical or leading edge
of epithelial cells upon activation by Cdc42-GTP [57, 62]. Accumulating evidence indicates that Cdc42 responds to and is activated
upon different mechanical loads such as hyperosmolarity, shear
stress, and intercellular increased tension [63]. Upon exposure to
mechanical loads, Cdc42 translocates from cytosol to the membrane and is concomitantly activated [64]. Activation of Cdc42 by
exchange of GDP for GTP triggers actin polymerization and generation of tension [65, 66]. Binding of activated Cdc42-GTP to the
CRIB domain of PAR6 favors the interaction with CRUMBS over
the interaction with PALS1 through a change in conformation of
the CRIB-PDZ domains of PAR6 [67]. Upon Cdc42-GTP binding, a portion of the flexible CRIB motif folds into a stable conformation with the PDZ domain [68], triggering an increase affinity
for the interaction with CRUMBS, and releasing the interaction
with PALS1. The modular nature of PAR6 may allow the mutually
exclusive interaction of CRUMBS and PALS1 with its PDZ
domains, regulating the assembly and localization of different
polarity complexes depending on the cellular context.
The localization of PAR6 to the plasma membrane depends on
both the PDZ and the PBM domains, as both deletions caused a
strong mislocalization of PAR6 to the cytosol. The PBM domain
binds with different affinities to the PDZ1 and PDZ3 of PAR3,
whose clustering is mediated by an increase in cortical tension as
previously mentioned [50]. The weak but multivalent interaction
of one PAR3 molecule with two PAR6 molecules might allow the
assembly a large cluster of PAR complexes at the cell membrane.
The formation of the large-scale cluster of PAR complexes can
facilitate the actomyosin dependent advective transport of several
PAR6 proteins during the establishment of polarity but also the
formation of large clusters made with several proteins such as
aPKC, PALS1, or CRUMBS that can serve different functions.
4.2 DLG
DLG is a MAGUK protein that presents an L27 domain, 3 PDZ
domains, an SH3 domain, a HOOK domain and a Guanylate like
domain. DLG is a member of the basolateral polarity complex
SCRIBBLE, and is involved in processes such as cell division, cell
migration and cell polarity [69] The N-terminal L27 domain interacts with the two L27 domains of calcium/calmodulin-dependent
serine protein kinase (CASK) [70]. CASK is a membrane-associated
guanylate kinase and a scaffolding protein, that has been
264
Elsa Bazellie ` res and Andre ´ Le Bivic
PAR6 is part of the Partitioning defective proteins in C. elegans, and
encodes a protein with PKC binding domain (PB1), a semiCdc42/Rac1 interactive binding (CRIB) and a PDZ domain
[57]. Recently a PDZ binding motif (PBM) was identified at its
C-terminal region [58]. PAR6 in many species is involved in cell
division, cell polarization, and cell migration, processes that are
characterized by changes in cellular forces [59–61].
PAR6 function is able to segregate to the apical or leading edge
of epithelial cells upon activation by Cdc42-GTP [57, 62]. Accumulating evidence indicates that Cdc42 responds to and is activated
upon different mechanical loads such as hyperosmolarity, shear
stress, and intercellular increased tension [63]. Upon exposure to
mechanical loads, Cdc42 translocates from cytosol to the membrane and is concomitantly activated [64]. Activation of Cdc42 by
exchange of GDP for GTP triggers actin polymerization and generation of tension [65, 66]. Binding of activated Cdc42-GTP to the
CRIB domain of PAR6 favors the interaction with CRUMBS over
the interaction with PALS1 through a change in conformation of
the CRIB-PDZ domains of PAR6 [67]. Upon Cdc42-GTP binding, a portion of the flexible CRIB motif folds into a stable conformation with the PDZ domain [68], triggering an increase affinity
for the interaction with CRUMBS, and releasing the interaction
with PALS1. The modular nature of PAR6 may allow the mutually
exclusive interaction of CRUMBS and PALS1 with its PDZ
domains, regulating the assembly and localization of different
polarity complexes depending on the cellular context.
The localization of PAR6 to the plasma membrane depends on
both the PDZ and the PBM domains, as both deletions caused a
strong mislocalization of PAR6 to the cytosol. The PBM domain
binds with different affinities to the PDZ1 and PDZ3 of PAR3,
whose clustering is mediated by an increase in cortical tension as
previously mentioned [50]. The weak but multivalent interaction
of one PAR3 molecule with two PAR6 molecules might allow the
assembly a large cluster of PAR complexes at the cell membrane.
The formation of the large-scale cluster of PAR complexes can
facilitate the actomyosin dependent advective transport of several
PAR6 proteins during the establishment of polarity but also the
formation of large clusters made with several proteins such as
aPKC, PALS1, or CRUMBS that can serve different functions.
4.2 DLG
DLG is a MAGUK protein that presents an L27 domain, 3 PDZ
domains, an SH3 domain, a HOOK domain and a Guanylate like
domain. DLG is a member of the basolateral polarity complex
SCRIBBLE, and is involved in processes such as cell division, cell
migration and cell polarity [69] The N-terminal L27 domain interacts with the two L27 domains of calcium/calmodulin-dependent
serine protein kinase (CASK) [70]. CASK is a membrane-associated
guanylate kinase and a scaffolding protein, that has been
264
Elsa Bazellie ` res and Andre ´ Le Bivic