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Mol Cell Biol, February 1998, p. 880-886, Vol. 18, No. 2
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Regulation of Sos Activity by Intramolecular
Interactions
Senena
Corbalan-Garcia,
Steluta M.
Margarit,
Dalia
Galron,
Shao-song
Yang, and
Dafna
Bar-Sagi*
Department of Molecular Genetics and
Microbiology, State University of New York at Stony Brook, Stony
Brook, New York 11794-8621
Received 25 June 1997/Returned for modification 20 August
1997/Accepted 24 October 1997
The guanine nucleotide exchange factor Sos mediates the coupling of
receptor tyrosine kinases to Ras activation. To investigate the
mechanisms that control Sos activity, we have analyzed the contribution
of various domains to its catalytic activity. Using human Sos1 (hSos1)
truncation mutants, we show that Sos proteins lacking either the amino
or the carboxyl terminus domain, or both, display a guanine nucleotide
exchange activity that is significantly higher compared with that of
the full-length protein. These results demonstrate that both the amino
and the carboxyl terminus domains of Sos are involved in the negative
regulation of its catalytic activity. Furthermore, in vitro Ras binding
experiments suggest that the amino and carboxyl terminus domains exert
negative allosteric control on the interaction of the Sos catalytic
domain with Ras. The guanine nucleotide exchange activity of hSos1 was
not augmented by growth factor stimulation, indicating that Sos
activity is constitutively maintained in a downregulated state.
Deletion of both the amino and the carboxyl terminus domains was
sufficient to activate the transforming potential of Sos. These
findings suggest a novel negative regulatory role for the amino
terminus domain of Sos and indicate a cooperation between the amino and the carboxyl terminus domains in the regulation of Sos activity.
*
Corresponding author. Mailing address: Department of
Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, NY 11794-5222. Phone: (516) 632-9737. Fax:
(516) 632-8891. E-mail: barsagi{at}pharm.sunysb.edu.

Present address: Dpto. de Bioquimica y Biologia Molecular (A),
Facultad de Veterinaria, Universidad de Murcia, E-30080 Murcia,
Spain.
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