The scaffold protein MEK Partner 1 is required for the survival of estrogen receptor positive breast cancer cells

Mihaela Marina,Limin Wang,Susan E Conrad

doi:10.1186/1478-811x-10-18

Abstract

MEK Partner 1 (MP1 or MAPKSP1) is a scaffold protein that has been reported to function in multiple signaling pathways, including the ERK, PAK and mTORC pathways. Several of these pathways influence the biology of breast cancer, but MP1’s functional significance in breast cancer cells has not been investigated. In this report, we demonstrate a requirement for MP1 expression in estrogen receptor (ER) positive breast cancer cells. MP1 is widely expressed in both ER-positive and negative breast cancer cell lines, and in non-tumorigenic mammary epithelial cell lines. However, inhibition of its expression using siRNA duplexes resulted in detachment and apoptosis of several ER-positive breast cancer cell lines, but not ER-negative breast cancer cells or non-tumorigenic mammary epithelial cells. Inhibition of MP1 expression in ER-positive MCF-7 cells did not affect ERK activity, but resulted in reduced Akt1 activity and reduced ER expression and activity. Inhibition of ER expression did not result in cell death, suggesting that decreased ER expression is not the cause of cell death. In contrast, pharmacological inhibition of PI3K signaling did induce cell death in MCF-7 cells, and expression of a constitutively active form of Akt1 partially rescued the cell death observed when the MP1 gene was silenced in these cells. Together, these results suggest that MP1 is required for pro-survival signaling from the PI3K/Akt pathway in ER-positive breast cancer cells.

Highlights

The small protein MEK Partner 1 (MP1, known as Map Kinase Scaffold Protein 1 and LAMTOR3) was originally identified as a scaffold protein that potentiates MAPK signaling by binding to MEK1 and ERK1 [1]
One clinical study identified MP1 as a gene associated with a poor prognosis signature in sporadic lymph-node negative breast cancer patients [16], but in our analysis high MP1 expression was not correlated with either time to distant metastasis or disease free survival
Inhibition of MP1 expression induces cell death and detachment of estrogen receptor (ER)-positive breast cancer cells To study the effect of inhibiting MP1 expression in breast cancer cells, short interfering RNA duplexes were used

Summary

Introduction

The small protein MEK Partner 1 (MP1, known as Map Kinase Scaffold Protein 1 and LAMTOR3) was originally identified as a scaffold protein that potentiates MAPK signaling by binding to MEK1 and ERK1 [1]. An MP1-p14-MEK1 complex is localized to late endosomes, and this localization is required for EGF-induced ERK1/2 signaling [2,3,4]. A second MP1-p14-p18 Ragulator complex is required for the recruitment of mTORC1 to the lysosomal surface, and is essential for amino acid-dependent signaling [5]. MP1 gene silencing in prostate cancer cells was associated with both decreased expression of paxillin and decreased number and turnover of focal adhesions at the migratory edge. Taken together, these data indicate that one function of MP1 in cell culture is related to cell spreading and migration

Methods

Results

Discussion

Conclusion