The C-terminal domain of Rac1 contains two motifs that control targeting and signaling specificity
The C-terminal domain of Rac1 contains two motifs that control targeting and signaling specificity
Rho-like GTPases control a wide range of cellular functions such as integrin- and cadherin-mediated adhesion, cell motility, and gene expression. The hypervariable C-terminal domain of these GTPases has been implicated in membrane association and effector binding. We found that cell-permeable peptides, encoding the C termini of Rac1, Rac2, RhoA, and Cdc42, interfere with GTPase signaling in a specific fashion in a variety of cellular models. Pull-down assays showed that the C terminus of Rac1 does not associate to either RhoGDI or to Pak. In contrast, the C terminus of Rac1 (but not Rac2 or Cdc42) binds to phosphatidylinositol 4,5-phosphate kinase (PIP5K) via amino acids 185-187 (RKR). Moreover, Rac1 associates to the adapter protein Crk via the N-terminal Src homology 3 (SH3) domain of Crk and the proline-rich stretch in the Rac1 C terminus. These differential interactions mediate Rac1 localization, as well as Rac1 signaling, toward membrane ruffling, cell-cell adhesion, and migration. These data show that the C-terminal, hypervariable domain of Rac1 encodes two distinct binding motifs for signaling proteins and regulates intracellular targeting and differential signaling in a unique and non-redundant fashion.
3T3 Cells Actins/chemistry Amino Acid Motifs Amino Acid Sequence Animals COS Cells Cell Adhesion Cell Line Cell Movement Dogs Fibroblasts/metabolism GTP Phosphohydrolases/chemistry HL-60 Cells Humans Membrane Microdomains/metabolism Mice Microscopy, Confocal Microscopy, Fluorescence Molecular Sequence Data Mutation Peptides/chemistry Protein Structure, Tertiary Sequence Homology, Amino Acid *Signal Transduction Time Factors rac1 GTP-Binding Protein/*chemistry src Homology Domains
39166-39175
van Hennik, P. B.
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ten Klooster, J. P.
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Halstead, J. R.
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Voermans, C.
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Anthony, E. C.
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Divecha, N.
5c2ad0f8-4ce7-405f-8a15-2fc4ab96d787
Hordijk, P. L.
2caa4048-06ec-472c-8ccf-baf8ee5ed3be
2003
van Hennik, P. B.
7039153e-bb57-462d-b32c-fa0913e61d99
ten Klooster, J. P.
df309507-23d6-43a7-8cf1-861b0fa8847c
Halstead, J. R.
019c9dab-c338-4f97-9318-353858ea82ac
Voermans, C.
3d6df707-5db9-4777-a1e6-75c277e52866
Anthony, E. C.
31cb7504-7cf7-467f-9806-b2debedcb9e5
Divecha, N.
5c2ad0f8-4ce7-405f-8a15-2fc4ab96d787
Hordijk, P. L.
2caa4048-06ec-472c-8ccf-baf8ee5ed3be
van Hennik, P. B., ten Klooster, J. P., Halstead, J. R., Voermans, C., Anthony, E. C., Divecha, N. and Hordijk, P. L.
(2003)
The C-terminal domain of Rac1 contains two motifs that control targeting and signaling specificity.
The Journal of Biological Chemistry, 278 (40), .
(doi:10.1074/jbc.M307001200).
Abstract
Rho-like GTPases control a wide range of cellular functions such as integrin- and cadherin-mediated adhesion, cell motility, and gene expression. The hypervariable C-terminal domain of these GTPases has been implicated in membrane association and effector binding. We found that cell-permeable peptides, encoding the C termini of Rac1, Rac2, RhoA, and Cdc42, interfere with GTPase signaling in a specific fashion in a variety of cellular models. Pull-down assays showed that the C terminus of Rac1 does not associate to either RhoGDI or to Pak. In contrast, the C terminus of Rac1 (but not Rac2 or Cdc42) binds to phosphatidylinositol 4,5-phosphate kinase (PIP5K) via amino acids 185-187 (RKR). Moreover, Rac1 associates to the adapter protein Crk via the N-terminal Src homology 3 (SH3) domain of Crk and the proline-rich stretch in the Rac1 C terminus. These differential interactions mediate Rac1 localization, as well as Rac1 signaling, toward membrane ruffling, cell-cell adhesion, and migration. These data show that the C-terminal, hypervariable domain of Rac1 encodes two distinct binding motifs for signaling proteins and regulates intracellular targeting and differential signaling in a unique and non-redundant fashion.
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e-pub ahead of print date: 21 July 2003
Published date: 2003
Additional Information:
van Hennik, Paula B ten Klooster, Jean Paul Halstead, Jon R Voermans, Carlijn Anthony, Eloise C Divecha, Nullin Hordijk, Peter L eng Research Support, Non-U.S. Gov't 2003/07/23 J Biol Chem. 2003 Oct 3;278(40):39166-75. doi: 10.1074/jbc.M307001200. Epub 2003 Jul 21.
Keywords:
3T3 Cells Actins/chemistry Amino Acid Motifs Amino Acid Sequence Animals COS Cells Cell Adhesion Cell Line Cell Movement Dogs Fibroblasts/metabolism GTP Phosphohydrolases/chemistry HL-60 Cells Humans Membrane Microdomains/metabolism Mice Microscopy, Confocal Microscopy, Fluorescence Molecular Sequence Data Mutation Peptides/chemistry Protein Structure, Tertiary Sequence Homology, Amino Acid *Signal Transduction Time Factors rac1 GTP-Binding Protein/*chemistry src Homology Domains
Identifiers
Local EPrints ID: 479384
URI: http://eprints.soton.ac.uk/id/eprint/479384
ISSN: 0021-9258
PURE UUID: a0b81d2b-db6b-4498-ab54-1fd40081518b
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Date deposited: 20 Jul 2023 17:39
Last modified: 17 Mar 2024 03:00
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Contributors
Author:
P. B. van Hennik
Author:
J. P. ten Klooster
Author:
J. R. Halstead
Author:
C. Voermans
Author:
E. C. Anthony
Author:
P. L. Hordijk
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