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Molecular and Cellular Biology, December 1998, p. 7038-7051, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

ASAP1, a Phospholipid-Dependent Arf GTPase-Activating Protein That Associates with and Is Phosphorylated by Src

Megan T. Brown,1 Josefa Andrade,2 Harish Radhakrishna,3 Julie G. Donaldson,3 Jonathan A. Cooper,1 and Paul A. Randazzo2,*

Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109,1 and Laboratory of Cell Biology, National Heart, Lung, and Blood Institute,3 and Laboratory of Cellular Oncology, Division of Basic Sciences, National Cancer Institute,2 Bethesda, Maryland 20892

Received 9 July 1998/Returned for modification 6 August 1998/Accepted 21 August 1998

Membrane trafficking is regulated in part by small GTP-binding proteins of the ADP-ribosylation factor (Arf) family. Arf function depends on the controlled exchange and hydrolysis of GTP. We have purified and cloned two variants of a 130-kDa phosphatidylinositol 4,5-biphosphate (PIP2)-dependent Arf1 GTPase-activating protein (GAP), which we call ASAP1a and ASAP1b. Both contain a pleckstrin homology (PH) domain, a zinc finger similar to that found in another Arf GAP, three ankyrin (ANK) repeats, a proline-rich region with alternative splicing and SH3 binding motifs, eight repeats of the sequence E/DLPPKP, and an SH3 domain. Together, the PH, zinc finger, and ANK repeat regions possess PIP2-dependent GAP activity on Arf1 and Arf5, less activity on Arf6, and no detectable activity on Arl2 in vitro. The cDNA for ASAP1 was independently identified in a screen for proteins that interact with the SH3 domain of the tyrosine kinase Src. ASAP1 associates in vitro with the SH3 domains of Src family members and with the Crk adapter protein. ASAP1 coprecipitates with Src from cell lysates and is phosphorylated on tyrosine residues in cells expressing activated Src. Both coimmunoprecipitation and tyrosine phosphorylation depend on the same proline-rich class II Src SH3 binding site required for in vitro association. By directly interacting with both Arfs and tyrosine kinases involved in regulating cell growth and cytoskeletal organization, ASAP1 could coordinate membrane remodeling events with these processes.

* Corresponding author. Mailing address: Laboratory of Cellular Oncology, Division of Basic Sciences, National Cancer Institute, 37 Convent Dr. MSC 4255, Bethesda, MD 20892-4255. Phone: (301) 496-3788. Fax: (301) 496-5839. E-mail: randazzo{at}helix.nih.gov.

Molecular and Cellular Biology, December 1998, p. 7038-7051, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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