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Molecular and Cellular Biology, November 2007, p. 7765-7770, Vol. 27, No. 22
0270-7306/07/$08.00+0     doi:10.1128/MCB.00965-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

RAPID REPORT

Biochemical and Functional Characterization of Germ Line KRAS Mutations{triangledown}

Suzanne Schubbert,1 Gideon Bollag,2 Natalya Lyubynska,1 Hoa Nguyen,2 Christian P. Kratz,3 Martin Zenker,4 Charlotte M. Niemeyer,3 Anders Molven,5,6 and Kevin Shannon1,7*

Department of Pediatrics, University of California, 513 Parnassus Avenue, HSE 302, San Francisco, California 94143,1 Plexxikon Inc., 91 Bolivar Dr., Berkeley, California,2 Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Mathildenstrasse 1, 79106 Freiburg, Germany,3 Institute of Human Genetics, University of Erlangen-Nuremberg, 91054 Erlangen, Germany,4 Section for Pathology, Gade Institute, University of Bergen, Bergen, Norway,5 Department of Pathology, Haukeland University Hospital, Bergen, Norway,6 Comprehensive Cancer Center, University of California, San Francisco, California7

Received 31 May 2007/ Returned for modification 6 July 2007/ Accepted 4 September 2007

ABSTRACT

Germ line missense mutations in HRAS and KRAS and in genes encoding molecules that function up- or downstream of Ras in cellular signaling networks cause a group of related developmental disorders that includes Costello syndrome, Noonan syndrome, and cardiofaciocutaneous syndrome. We performed detailed biochemical and functional studies of three mutant K-Ras proteins (P34R, D153V, and F156L) found in individuals with Noonan syndrome and cardiofaciocutaneous syndrome. Mutant K-Ras proteins demonstrate a range of gain-of-function effects in different cell types, and biochemical analysis supports the idea that the intrinsic Ras guanosine nucleotide triphosphatase (GTPase) activity, the responsiveness of these proteins to GTPase-activating proteins, and guanine nucleotide dissociation all regulate developmental programs in vivo.

* Corresponding author. Mailing address: University of California, San Francisco, 513 Parnassus Ave., San Francisco, CA 94143. Phone: (415) 476-7932. Fax: (415) 502-5127. E-mail: shannonk{at}peds.ucsf.edu

FOOTNOTES

{triangledown} Published ahead of print on 17 September 2007.

Molecular and Cellular Biology, November 2007, p. 7765-7770, Vol. 27, No. 22
0270-7306/07/$08.00+0     doi:10.1128/MCB.00965-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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