Flipping the Switch Minireview The Structural Basis for Signaling through the CRIB Motif

family of CRIB domain–containing proteins is represented by the nonreceptor tyrosine kinases ACK-1 (Manser et al., 1993) and ACK-2 (Yang et al., 1997), which are highly specific targets for Cdc42. While these tyrosine kinases have yet to be linked to a specific pathological condition, it is likely that they will play important roles in neuronal cell function as they are highly expressed in brain and have been implicated in integrin-coupled signaling. The Rho family GTPases function as tightly regulated There seems little doubt that understanding how the molecular switches governing critical cellular functions. activated form of Cdc42 or Rac triggers the activation of The activity of these proteins is controlled by their GTP its CRIB domain–containing target/effectors will provide binding and hydrolytic cycle such that binding of cellular important molecular insights into the signaling functions GTP induces an active conformation capable of inter-of these GTP binding proteins. A remarkable feature of acting with downstream effector molecules and initiat-the GTP binding proteins in their capacity as signaling ing a cellular response. The conserved CRIB (for Cdc42-switches is the subtlety of the structural changes that and Rac-interactive binding) motif is the hallmark of an distinguish their GDP-bound " off " state from their GTP-important subset of effectors for Cdc42 and Rac (Figure bound " on " (active) state. These structural changes are 1). This conserved sequence forms part of the limit bind-basically confined to two limit regions denoted as switch ing domain for Cdc42 and Rac (also called the PBD I and switch II. With the recent emergence of the struc-for p21 binding domain, and GBD for GTPase binding tures for the inactive and active states of CRIB domain– domain), and residues of the CRIB sequence are essen-containing targets (reviewed below), we see that while tial for the interaction of these effectors with GTP-bound the conformational alterations in the GTP binding pro-Cdc42 or Rac (Rudolph et al., 1998; Owen et al., 2000). teins are relatively minor, these changes lead to dra-This region was first identified by Lim and colleagues matic structural alterations in their signaling targets. As (Manser et al., 1994) as a conserved sequence in two will become evident below, this type of conformational Cdc42 effectors, the serine/threonine kinase PAK-1 change/amplification has important consequences for (p21-activated kinase 1) and the tyrosine kinase ACK-1 the initiation of signal propagation. (activated Cdc42-associated kinase 1). Subsequently, In a recent issue of Cell, the Mayer …