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Molecular and Cellular Biology, February 1999, p. 1334-1345, Vol. 19, No. 2
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Activation of the Lbc Rho Exchange Factor Proto-Oncogene by Truncation of an Extended C Terminus That Regulates Transformation and Targeting

Paola Sterpetti,1 Andrew A. Hack,1,dagger Mariam P. Bashar,1 Brian Park,1 Sou-De Cheng,2 Joan H. M. Knoll,2,3 Takeshi Urano,4,Dagger Larry A. Feig,4 and Deniz Toksoz1,*

Department of Physiology1 and Department of Biochemistry,4 Tufts University School of Medicine, Boston, Massachusetts 02111, and Division of Genetics, Children's Hospital,2 and Department of Pathology, Beth Israel-Deaconess Medical Center,3 Harvard Medical School, Boston, Massachusetts 02215

Received 11 May 1998/Returned for modification 17 June 1998/Accepted 3 November 1998

The human lbc oncogene product is a guanine nucleotide exchange factor that specifically activates the Rho small GTP binding protein, thus resulting in biologically active, GTP-bound Rho, which in turn mediates actin cytoskeletal reorganization, gene transcription, and entry into the mitotic S phase. In order to elucidate the mechanism of onco-Lbc transformation, here we report that while proto- and onco-lbc cDNAs encode identical N-terminal dbl oncogene homology (DH) and pleckstrin homology (PH) domains, proto-Lbc encodes a novel C terminus absent in the oncoprotein that includes a predicted alpha -helical region homologous to cyto-matrix proteins, followed by a proline-rich region. The lbc proto-oncogene maps to chromosome 15, and onco-lbc represents a fusion of the lbc proto-oncogene N terminus with a short, unrelated C-terminal sequence from chromosome 7. Both onco- and proto-Lbc can promote formation of GTP-bound Rho in vivo. Proto-Lbc transforming activity is much reduced compared to that of onco-Lbc, and a significant increase in transforming activity requires truncation of both the alpha -helical and proline-rich regions in the proto-Lbc C terminus. Deletion of the chromosome 7-derived C terminus of onco-Lbc does not destroy transforming activity, demonstrating that it is loss of the proto-Lbc C terminus, rather than gain of an unrelated C-terminus by onco-Lbc, that confers transforming activity. Mutations of onco-Lbc DH and PH domains demonstrate that both domains are necessary for full transforming activity. The proto-Lbc product localizes to the particulate (membrane) fraction, while the majority of the onco-Lbc product is cytosolic, and mutations of the PH domain do not affect this localization. The proto-Lbc C-terminus alone localizes predominantly to the particulate fraction, indicating that the C terminus may play a major role in the correct subcellular localization of proto-Lbc, thus providing a mechanism for regulating Lbc oncogenic potential.

* Corresponding author. Mailing address: Department of Physiology, Tufts University School of Medicine, Boston, MA 02111. Phone: (617) 636-6719. Fax: (617) 636-0445. E-mail: dtoksoz{at}infonet.tufts.edu.

dagger Present address: MSTP, Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637.

Dagger Present address: Second Department of Biochemistry, Nagoya University School of Medicine, Nagoya 466, Japan.

Molecular and Cellular Biology, February 1999, p. 1334-1345, Vol. 19, No. 2
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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