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proteins 2 and 3 (Arp2/3) complex and leads to the formation of the actin pedestals
( Figure 4.2 B) ( Lommel et al., 2001 ). However, some EPEC strains lacking Tir
Y474 are still capable of promoting actin polymerization. These Nck-independent
modes of recruiting N-WASP are attributed to phosphorylation of Y454 ( Campel-
lone and Leong, 2005 ), and to the TccP (Tir-cytoskeleton coupling protein) ( Whale
et al., 2006 ) effectors one and two (also known as EspF U and EspF M ). These effec-
tors bind the GTPase binding domain of N-WASP ( Campellone et al., 2004 ). More
recently, phosphorylation of Y474 has been shown to recruit redundant kinases.
The polyproline region of EspF interacts with the SH3 domains of these kinases,
while the Y474 site interacts with the SH2 domains ( Bommarius et al., 2007 ).
This activity constitutes a positive feedback loop in which the recruited kinases
phosphorylate other Tir molecules.
Recent studies have highlighted the importance of other T3S effectors
in remodeling the host cytoskeleton by modulating Rho GTPases. EspF is a
206-amino-acid protein, the C-terminus of which contains three identical
repeats of a proline-rich sequence that resembles those recognized by eukary-
otic signaling proteins containing SH3 domains ( Donnenberg et al., 1997 ).
The C-terminus of each repeat also contains an N-WASP binding motif ( Alto
et al., 2007 ). EspF activates the Arp2/3 complex and induces actin polymeriza-
tion in vitro ( Weflen et al., 2009 ). Map and EspM display guanine exchange
factor (GEF) activity ( Huang et al., 2009 ; Arbeloa et al., 2010 ). Map and EspT
activate Cdc42 activity, which induces filopodia formation ( Kenny et al., 2002 ;
Berger et al., 2009 ), while EspM activates RhoA, inducing actin stress fibers
( Alto et al., 2006 ; Arbeloa et al., 2008 ). Other T3S effectors involved in ped-
estal dynamics are EspH and EspV ( Tu et al., 2003 ; Arbeloa et al., 2011 ).
The mechanism by which EspV modulates the cytoskeleton is unknown. EspH
competitively binds to tandem DH-PH domains of endogenous Dbl-homol-
ogy and pleckstrin-homology RhoGEFs and prevents Rho activation ( Dong
et al., 2010 ). Thus, EPEC strains secrete effectors that inactivate endogenous
RhoGEFs, in addition to secreting their own GEF to hijack the host signaling
pathway. EspH also stimulates actin polymerization by recruiting N-WASP
and the Arp2/3 complex independently of the tyrosine phosphorylation of Tir
but via the C-terminus of Tir and the WH1 domain of N-WASP ( Wong et al.,
2012a,b ).
Disruption of the epithelial barrier
The apical junction complex, which consists of tight junctions (TJ) and adherent
junctions connecting neighboring cells, is critical for separation of intestinal tis-
sues from luminal contents ( Harhaj and Antonetti, 2004 ). The TJ is comprised
of three different transmembrane proteins; occludin, claudins, and junctional
adhesion molecule (JAM). These proteins are attached to actin filaments and
MLC via the zonula occludens (ZO) family of proteins, which are peripheral
membrane proteins associated with the cytoplasmic surface of TJ and adherent
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