title: Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) interacts with PELP1 and activates MAPK.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, 77030, USA.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Rayala
authors.forename: Petra den
authors.initials: Pd
authors.lastname: Hollander
authors.forename: Seetharaman
authors.initials: S
authors.lastname: Balasenthil
authors.forename: Poonam R
authors.initials: PR
authors.lastname: Molli
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bean
authors.forename: Ratna K
authors.initials: RK
authors.lastname: Vadlamudi
authors.forename: Rui-An
authors.initials: RA
authors.lastname: Wang
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000737:chemistry; D002478:Cells, Cultured; D056970:Co-Repressor Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000502:physiology*; D011960:Receptors, Estrogen / Q000235:genetics; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors
chemical_list: D056970:Co-Repressor Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C438485:PELP1 protein, human; D010750:Phosphoproteins; D011960:Receptors, Estrogen; D015534:Trans-Activators; D014157:Transcription Factors; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases