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J. Biol. Chem., Vol. 281, Issue 7, 4395-4403, February 17, 2006

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Hepatocyte Growth Factor-regulated Tyrosine Kinase Substrate (HRS) Interacts with PELP1 and Activates MAPK^*

Suresh K. Rayala, Petra den Hollander, Seetharaman Balasenthil, Poonam R. Molli, Andrew J. Bean¹, Ratna K. Vadlamudi^¶, Rui-An Wang, and Rakesh Kumar²

From the Department of Molecular and Cellular Oncology, the University of Texas M. D. Anderson Cancer Center and the Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, Texas 77030 and the ^¶Department of Genetics, Stanley S. Scott Cancer Center, Louisiana State University Health Science Center, New Orleans, Louisiana 70112

PELP1 (proline-, glutamic acid-, and leucine-rich protein-1) (also known as the modulator of nongenomic activity of estrogen receptor) plays a role in genomic functions of the estrogen receptor via histone interactions and in nongenomic functions via its influence on the MAPK-Src pathway. However, recent studies have shown that differential compartmentalization of PELP1 could play a crucial role in modulating the status of nongenomic signaling by using molecular mechanisms that remain poorly understood. Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) is an early endosomal protein that plays a role in regulating the trafficking of growth factor-receptor complexes through early endosomes. By using a yeast two-hybrid screen, we identified HRS as a novel PELP1-binding protein providing evidence of a physiologic interaction between HRS and PELP1. The noted HRS-PELP1 interaction was accompanied by inhibition of the basal coactivator function of PELP1 upon estrogen receptor transactivation. HRS was found to sequester PELP1 in the cytoplasm, leading to the activation of MAPK in a manner that is dependent on the epidermal growth factor receptor but independent of the estrogen receptor, Shc, and Src. In addition, stimulation of MAPK and the subsequent activation of its downstream effector pathway, Elk-1, by HRS or PELP1 were found to depend on the presence of endogenous PELP1 or HRS. Furthermore, HRS was overexpressed and correlated well with the cytoplasmic PELP1, increased MAPK, and EGFR status in breast tumors. These findings highlight a novel role of HRS in up-regulating MAPK, presumably involving interaction with PELP1.

Received for publication, September 21, 2005 , and in revised form, December 7, 2005.

^* This work was supported in part by National Institutes of Health Grants CA90970 and CA98823 (to R. K.). 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 Supported by National Institutes of Health Grant MH05892.

² To whom correspondence and requests for reprints should be addressed: Dept. of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-745-3558; Fax: 713-745-3792; E-mail: rkumar{at}mdanderson.org.

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