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J Biol Chem, Vol. 273, Issue 34, 21512-21518, August 21, 1998
From the Department of Immunology, The Scripps Research Institute,
La Jolla, California 92037
The Rho family GTPases, Rac1 and Rac2, regulate a
variety of cellular functions including cytoskeletal reorganization,
the generation of reactive oxygen species, G1 cell
cycle progression and, in concert with Ras, oncogenic transformation.
Among the many putative protein targets identified for Rac (and/or
Cdc42), the Ser/Thr kinase p21-activated kinase (PAK) is a prime
candidate for mediating some of Rac's cellular effects. This report
shows that Rac1 binds to and stimulates the kinase activity of PAK1 approximately 2- and 4-5-fold, respectively, better than Rac2. Mutational analysis was employed to determine the structural elements on Rac and PAK that are important for optimal binding and activation. The most notable difference between the highly homologous Rac isomers
is the composition of their C-terminal polybasic domains. Mutation of
these six basic residues in Rac1 to neutral amino acids dramatically
decreased the ability of Rac1 to bind PAK1 and almost completely
abolished its ability to stimulate PAK activity. Moreover, replacing
the highly charged polybasic domain of Rac1 with the less charged
domain of Rac2 (and vice versa) completely reversed the PAK
binding/activation properties of the two Rac isomers. Thus, polybasic
domain differences account for the disparate abilities of Rac1 and Rac2
to activate PAK. PAK proteins also contain a basic region, consisting
of three contiguous lysine residues
(Lys66-Lys67-Lys68), which lies
outside of the previously identified Cdc42/Rac-binding domain. Mutation
of these Lys residues to neutral residues decreased PAK binding to
activated Rac1 and Rac2 (but not Cdc42) and greatly reduced PAK1
activation by Rac1, Rac2, and Cdc42 proteins in vivo. In
contrast, mutation of lysines 66-68 to basic Arg residues did not
decrease (and in some cases enhanced) the ability of Rac1, Rac2, and
Cdc42 to bind and activate PAK1. Our studies suggest that the polybasic
domain of Rac is a novel effector domain that may allow the two Rac
isomers to activate different effector proteins. In addition, our
results indicate that a basic region in PAK is required for PAK
activation and that binding of Rac/Cdc42 to PAK is not sufficient for
kinase activation.
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