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Figure 9.2 IRSp53 transmits signals from both Rac and Cdc42 for lamellipodia and
filopodia formation. IRSp53 has an SH3 domain at C-terminus, a centrally located GBD/
CRIB motif and an RCB (Rac binding site) at the N-terminus. IRSp53 binds to WAVE2
through its SH3 domain and to Rac through its RCB domain (upper panel), leading to
lamellipodium formation. IRSp53 also binds to Cdc42 through its GDB/CRIB motif and
associates with Mena/Ena through its C-terminal SH3 domain (lower panel), leading to
filopodium formation
et al., 2000; Miki and Takenawa, 2002) (Figure 9.2). Curiously, IRSp53 was
found to bind predominantly to WAVE2, and binding to WAVE1 and 3 was
very weak. This pathway presumably plays a significant role in several kinds
of cells because dominant-negative (DSH3) IRSp53 inhibits Rac-induced
formation of lamellipodia (Miki et al., 2000). However, it was recently
reported that IRSp53 has a CRIB domain at its centre, to which Cdc42 can
bind (Krugmann et al., 2001; Govind et al., 2001). Addition of Cdc42 to cells
expressing IRSp53 induces formation of filopodia but not lamellipodia
(Figure 9.2), suggesting that IRSp53 alone does not directly influence the
shape of actin structures but instead transmits upstream signals to down-
stream proteins involved in actin assembly. In this case, Rac or Cdc42 rather
than IRSp53 may determine the shape of actin filaments.
Eden et al. (2002) recently proposed a new mechanism of activation of
WAVE1 (Figure 9.3). They isolated WAVE1 protein complexes from bovine
brain and identified the protein components by mass spectrometry. This
complex contained WAVE1, PIR121 (p53-inducible messenger RNA),
