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Molecular and Cellular Biology, August 2005, p. 6314-6329, Vol. 25, No. 15
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.15.6314-6329.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Extracellular Signal-Regulated Kinase 1 Interacts with and Phosphorylates CdGAP at an Important Regulatory Site

Joseph Tcherkezian, Eric I. Danek, Sarah Jenna, Ibtissem Triki, and Nathalie Lamarche-Vane^*

Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada H3A 2B2

Received 14 January 2005/ Returned for modification 10 February 2005/ Accepted 3 May 2005

Rho GTPases regulate multiple cellular processes affecting both cell proliferation and cytoskeletal dynamics. Their cycling between inactive GDP- and active GTP-bound states is tightly regulated by guanine nucleotide exchange factors and GTPase-activating proteins (GAPs). We have previously identified CdGAP (for Cdc42 GTPase-activating protein) as a specific GAP for Rac1 and Cdc42. CdGAP consists of an N-terminal RhoGAP domain and a C-terminal proline-rich region. In addition, CdGAP is a member of the impressively large number of mammalian RhoGAP proteins that is well conserved among both vertebrates and invertebrates. In mice, we find two predominant isoforms of CdGAP differentially expressed in specific tissues. We report here that CdGAP is highly phosphorylated in vivo on serine and threonine residues. We find that CdGAP is phosphorylated downstream of the MEK-extracellular signal-regulated kinase (ERK) pathway in response to serum or platelet-derived growth factor stimulation. Furthermore, CdGAP interacts with and is phosphorylated by ERK-1 and RSK-1 in vitro. A putative DEF (docking for ERK FXFP) domain located in the proline-rich region of CdGAP is required for efficient binding and phosphorylation by ERK1/2. We identify Thr⁷⁷⁶ as an in vivo target site of ERK1/2 and as an important regulatory site of CdGAP activity. Together, these data suggest that CdGAP is a novel substrate of ERK1/2 and mediates cross talk between the Ras/mitogen-activated protein kinase pathway and regulation of Rac1 activity.

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* Corresponding author. Mailing address: Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada H3A 2B2. Phone: (514) 398-1784. Fax: (514) 398-5047. E-mail: nathalie.lamarche{at}mcgill.ca.

Present address: RPMPN, McGill University, Montreal, Quebec, Canada H3A 2B2.

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Molecular and Cellular Biology, August 2005, p. 6314-6329, Vol. 25, No. 15
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.15.6314-6329.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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