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(Received for publication, May 7, 1996, and in revised form, June 19, 1996)
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From the Departments of Biochemistry, Cdc42 is a Ras-related GTP-binding protein that
has been implicated in the regulation of the actin cytoskeleton and
cell morphology. In this study, we have identified a protein with a
molecular mass ~180 kDa from rabbit liver cytosol (designated p180),
which binds preferentially to the GTP- and guanosine
5
Molecular and
Cell Biology, and Pharmacology, Veterinary Medical Center, Cornell
University, Ithaca, New York 14853
-3-O-(thio)triphosphate-bound forms of Cdc42. Binding of
p180 to GTP-bound Cdc42 maintains it in the GTP-bound state. Another
cytosolic protein, with an apparent molecular mass of 175 kDa (p175),
was also found to interact with Cdc42, but this association showed less
dependence on guanine nucleotides. Both p180 and p175 were capable of
binding to Rac1 but not to RhoA or Ha-Ras. The limit functional domain
of the Cdc42-GAP protein did not compete with p180 or p175 for binding
to Cdc42. However, the Cdc42-binding domain from mPAK-3, a member of
the PAK (p21 activated kinase) family of serine/threonine kinases,
competed with both proteins. The binding of p180 or p175 was inhibited
by mutations of the putative effector loop of Cdc42. p180 and p175 also
bound less effectively to a Cdc42/Ras chimera in which loop 8 from Ras
was substituted for the predicted loop 8 in Cdc42 that includes a
13-amino acid insert present in all Rho family members but absent in
Ras. Microsequencing of a p180 peptide revealed 92% identity with the
human IQGAP1 protein, while two peptides derived from p175 were 89 and
100% identical to human IQGAP2. These findings identify IQGAP1 and
IQGAP2 as a new class of target/effectors that utilize both regions of
the switch I domain and an insert region distinct to Rho proteins for
binding to Cdc42.
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L. Van Aelst and C. D'Souza-Schorey Rho GTPases and signaling networks Genes & Dev., September 15, 1997; 11(18): 2295 - 2322. [Full Text] [PDF]
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S. H. Zigmond, M. Joyce, J. Borleis, G. M. Bokoch, and P. N. Devreotes Regulation of Actin Polymerization in Cell-free Systems by GTPgamma S and Cdc42 J. Cell Biol., July 28, 1997; 138(2): 363 - 374. [Abstract] [Full Text] [PDF]
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A.-M. Bashour, A. T. Fullerton, M. J. Hart, and G. S. Bloom IQGAP1, a Rac- and Cdc42-binding Protein, Directly Binds and Cross-links Microfilaments J. Cell Biol., June 30, 1997; 137(7): 1555 - 1566. [Abstract] [Full Text] [PDF]
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J. L. Joyal, R. S. Annan, Y.-D. Ho, M. E. Huddleston, S. A. Carr, M. J. Hart, and D. B. Sacks Calmodulin Modulates the Interaction between IQGAP1 and Cdc42. IDENTIFICATION OF IQGAP1 BY NANOELECTROSPRAY TANDEM MASS SPECTROMETRY J. Biol. Chem., June 13, 1997; 272(24): 15419 - 15425. [Abstract] [Full Text] [PDF]
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H. Adachi, Y. Takahashi, T. Hasebe, M. Shirouzu, S. Yokoyama, and K. Sutoh Dictyostelium IQGAP-related Protein Specifically Involved in the Completion of Cytokinesis J. Cell Biol., May 19, 1997; 137(4): 891 - 898. [Abstract] [Full Text] [PDF]
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S. J. Walker, W.-J. Wu, R. A. Cerione, and H. A. Brown Activation of Phospholipase D1 by Cdc42 Requires the Rho Insert Region J. Biol. Chem., May 19, 2000; 275(21): 15665 - 15668. [Abstract] [Full Text] [PDF]
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S. H. Kim, Z. Li, and D. B. Sacks E-cadherin-mediated Cell-Cell Attachment Activates Cdc42 J. Biol. Chem., November 17, 2000; 275(47): 36999 - 37005. [Abstract] [Full Text] [PDF]
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Q. Feng, J. G. Albeck, R. A. Cerione, and W. Yang Regulation of the Cool/Pix Proteins. KEY BINDING PARTNERS OF THE Cdc42/Rac TARGETS, THE p21-ACTIVATED KINASES J. Biol. Chem., February 8, 2002; 277(7): 5644 - 5650. [Abstract] [Full Text] [PDF]
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