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Molecular and Cellular Biology, November 2002, p. 7953-7966, Vol. 22, No. 22
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.22.7953-7966.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Cysteine-Rich Sprouty Translocation Domain Targets Mitogen-Activated Protein Kinase Inhibitory Proteins to Phosphatidylinositol 4,5-Bisphosphate in Plasma Membranes

Jormay Lim, Permeen Yusoff, Esther Sook Miin Wong, Sumana Chandramouli, Dieu-Hung Lao, Chee Wai Fong, and Graeme R. Guy*

Signal Transduction Laboratory, Institute of Molecular and Cell Biology, National University of Singapore, Singapore 117 609, Singapore

Received 11 March 2002/ Returned for modification 22 April 2002/ Accepted 12 August 2002

Sprouty (Spry) proteins have been revealed as inhibitors of the Ras/mitogen-activated protein kinase (MAPK) cascade, a pathway crucial for developmental processes initiated by activation of various receptor tyrosine kinases. In COS-1 and Swiss 3T3 cells, all Spry isoforms translocate to the plasma membrane, notably ruffles, following activation. Here we show that microinjection of active Rac induced the translocation of Spry isoforms, indicating that the target of the Spry translocation domain (SpryTD) is downstream of active Rac. Targeted disruption of actin polymerization revealed that the SpryTD target appeared upstream of cytoskeletal rearrangements. Accumulated evidence indicated that phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] is the likely SpryTD target. Human Spry2TD (hSpry2TD) binds to PtdIns(4,5)P2 in vesicle-binding assays. hSpry2TD colocalizes with the pleckstrin homology domain of phospholipase C{delta}, which binds PtdIns(4,5)P2. The plasma membrane localization of hSpry2TD was abolished in ionomycin-treated MDCK cells or when PtdIns(4,5)P2 was specifically dephosphorylated by overexpression of an engineered, green fluorescent protein-tagged inositol 5-phosphatase. Similarly, Spred, a novel Ras/MAPK inhibitor recently found to contain the conserved cysteine-rich SpryTD, also translocated to peripheral membranes and bound to PtdIns(4,5)P2. Alignment of the Spry and Spred proteins led us to identify a translocation-defective point mutant, hSpry2 D252. Targeting of hSpry2 to PtdIns(4,5)P2 was shown to be essential for the down-regulation of Ras/MAPK signaling.

* Corresponding author. Mailing address: Signal Transduction Laboratory, Institute of Molecular and Cell Biology, National University of Singapore, 30 Medical Dr., Singapore 117 609, Singapore. Phone: (65) 6874 3794. Fax: (65) 6779 1117. E-mail: mcbgg{at}imcb.nus.edu.sg.

Molecular and Cellular Biology, November 2002, p. 7953-7966, Vol. 22, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.22.7953-7966.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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