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J. Biol. Chem., Vol. 282, Issue 14, 10432-10440, April 6, 2007

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Characterization of a Novel Tripartite Nuclear Localization Sequence in the EGFR Family^*

From the Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030

Aberrant expression of epidermal growth factor receptor (EGFR) is present in many human tumors. Several reports have shown that EGFR is translocated into the nucleus during liver regeneration and in several types of cells and tissues such as placenta and thyroid. Nuclear EGFR is associated with transcription, DNA synthesis, and DNA repair activity and serves as a prognostic marker in breast carcinoma and oropharyngeal squamous cell cancer. However, the nuclear localization sequence (NLS) of EGFR has not been extensively examined. In this study, we have shown that the juxtamembrane region of EGFR harbors a putative NLS with three clusters of basic amino acids (RRRHIVRKRTLRR (amino acids 645–657)) that mediates the nuclear localization of EGFR. We found that this newly characterized tripartite NLS is conserved among the EGFR family members (EGFR, ErbB2, ErbB3, and ErbB4) and is able to move each to the nucleus. Further, this tripartite NLS could also mediate the nuclear localization of other known cytoplasmic proteins such as pyruvate kinase. We have demonstrated that mutating one of the three basic amino acid clusters (R or K A) leads to significant impairment of the nuclear localization of EGFR and that of a green fluorescent protein-pyruvate kinase-NLS reporter protein. Our results show that this tripartite NLS is distinct from the traditional mono- and bipartite NLS and reveal a mechanism that could account for the nuclear localization of membrane receptors.

Received for publication, October 25, 2006 , and in revised form, February 2, 2007.

^* This study was supported, in part, by Grant CA109311 from the National Institutes of Health (NIH) and by the National Breast Cancer Foundation, Inc. (to M.-C. H.) and by NIH Cancer Center Support Grant CA16672 (to M. D. Anderson). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Department of Molecular and Cellular Oncology, Unit 79, The University of Texas M. D. Anderson Cancer Ctr., 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-792-3668; E-mail: mhung{at}mdanderson.org.

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