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Molecular and Cellular Biology, October 2000, p. 7363-7377, Vol. 20, No. 19
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

c-Src Signaling Induced by the Adapters Sin and Cas Is Mediated by Rap1 GTPase†

Luzhou Xing,1 Chang Ge,1 Ross Zeltser,1 Gregory Maskevitch,1 Bruce J. Mayer,2 and Konstantina Alexandropoulos1,*

Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York 10032,1 and The Children's Hospital, Boston, Massachusetts 021152

Received 24 March 2000/Returned for modification 24 May 2000/Accepted 29 June 2000

Oncogenic Src proteins have been extensively studied to gain insight into the signaling mechanisms of Src. To better understand signaling through wild-type Src, we used an approach that involves activation of Src signaling through the binding of physiologic ligands to the Src SH3 domain. To this end, we used full-length and truncated versions of the multiadapter molecules Cas and Sin to activate c-Src, and we examined the intracellular pathways that mediate Src signaling under these conditions. We show that although all proteins bind to and are phosphorylated by c-Src, quantitative differences exist in the ability of the different ligands to activate c-Src signaling. In addition, we show that Sin- and Cas-induced Src signaling, as assayed by transcriptional activation, is exclusively mediated through a pathway that involves the adapter Crk and the GTP-binding protein Rap1. These data are in contrast to previous observations showing Ras to mediate signaling downstream of transforming Src alleles. In our system, we found that signaling through the oncogenic SrcY527 mutant is indeed mediated by Ras. In addition, we found that Rap1 also mediates oncogenic Src signaling. Our results show for the first time that Rap1 mediates c-Src kinase signaling and reveal mechanistic differences in the signaling properties of wild-type and transforming Src proteins.

* Corresponding author. Mailing address: Department of Pharmacology, College of Physicians and Surgeons of Columbia University, PH 7W Rm. 318, 630 West 168th St., New York, NY 10027. Phone: (212) 305-2705. Fax: (212) 305-8780. E-mail: ka141{at}columbia.edu.

dagger This report is dedicated to the memory of Eugenia Spanopoulou, Andrew Hotchev, and Platon Spanopoulos-Hotchev. Delta varepsilon nu sigma alpha sigmav xi varepsilon chi nu omega .

Molecular and Cellular Biology, October 2000, p. 7363-7377, Vol. 20, No. 19
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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