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J Biol Chem, Vol. 273, Issue 14, 8137-8144, April 3, 1998
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From the Departments of p21-activated kinases (PAKs) are serine/threonine
kinases that have been identified as targets for the small GTPases Rac
and Cdc42. PAKs have been implicated in cytoskeletal regulation,
stimulation of mitogen-activated protein kinase cascades, and in
control of the phagocyte NADPH oxidase. Membrane targeting of PAK1
induced increased kinase activity in a GTPase-independent manner,
suggesting that other mechanisms for PAK regulation exist. We observed
concentration- and time-dependent activation of PAK1 by
sphingosine and several related long chain sphingoid bases but not by
ceramides or a variety of other lipids. Although phospholipids were
generally ineffective, phosphatidic acid and phosphatidylinositol also
had stimulatory effects on PAK1. Lipid stimulation induced a similar
level of PAK1 activity as did stimulation by GTPases, and the patterns of PAK1 autophosphorylation determined after partial tryptic digestion and two-dimensional peptide analysis were similar with each class of
activator. Lipid stimulation of PAK1 activity was dependent upon intact
PAK kinase activity, as indicated by studies with a kinase-dead PAK1
mutant. Treatment of COS-7 cells expressing wild type PAK1 with
sphingosine, fumonisin B, or sphingomyelinase, all of which are able to
elevate the levels of free sphingosine, induced increased activity of
PAK1 as determined using a p47phox peptide substrate. Studies
using PAK1 mutants suggest that lipids act at a site overlapping or
identical to the GTPase-binding domain on PAK. The inactive sphingosine
derivative N,N-dimethylsphingosine was an effective
inhibitor of PAK1 activation in response to either sphingosine or
Cdc42. Our results demonstrate a novel GTPase-independent mechanism of
PAK activation and, additionally, suggest that PAK(s) may be important
mediators of the biological effects of sphingolipids.
Immunology and
§ Cell Biology, The Scripps Research Institute,
La Jolla, California 92037 and the ** Department of
Biochemistry and Molecular Biology, Georgetown University Medical
Center, Washington, D. C. 20007
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F. Yang, X. Li, M. Sharma, M. Zarnegar, B. Lim, and Z. Sun Androgen Receptor Specifically Interacts with a Novel p21-activated Kinase, PAK6 J. Biol. Chem., April 27, 2001; 276(18): 15345 - 15353. [Abstract] [Full Text] [PDF]
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U. Schmitz, K. Thommes, I. Beier, W. Wagner, A. Sachinidis, R. Dusing, and H. Vetter Angiotensin II-induced Stimulation of p21-activated Kinase and c-Jun NH2-terminal Kinase Is Mediated by Rac1 and Nck J. Biol. Chem., June 15, 2001; 276(25): 22003 - 22010. [Abstract] [Full Text] [PDF]
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Y. Banno, Y. Takuwa, Y. Akao, H. Okamoto, Y. Osawa, T. Naganawa, S. Nakashima, P.-G. Suh, and Y. Nozawa Involvement of Phospholipase D in Sphingosine 1-Phosphate-induced Activation of Phosphatidylinositol 3-Kinase and Akt in Chinese Hamster Ovary Cells Overexpressing EDG3 J. Biol. Chem., September 14, 2001; 276(38): 35622 - 35628. [Abstract] [Full Text] [PDF]
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C. C. King, F. T. Zenke, P. E. Dawson, E. M. Dutil, A. C. Newton, B. A. Hemmings, and G. M. Bokoch Sphingosine Is a Novel Activator of 3-Phosphoinositide-dependent Kinase 1 J. Biol. Chem., June 9, 2000; 275(24): 18108 - 18113. [Abstract] [Full Text] [PDF]
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