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

The small protein MEK Partner 1 (MP1, also 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]. MP1 interacts with another small protein p14, and together these two proteins are localized to endomembrane compartments as part of larger signaling complexes. For example, an MP1-p14-MEK1 complex is localized to late endosomes, and this localization is required for EGF-induced ERK1/2 signaling [2-4]. 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]. In addition to these trimeric complexes, MP1 has been reported to bind PAK1 at the plasma membrane, and the MP1-PAK1 interaction is required for MEK phosphorylation by PAK1 in the absence of Raf [6,7]. Thus, MP1 can regulate the function of several intracellular kinases in different subcellular locations.Both in vitro and in vivo approaches have been taken to investigate the biological functions of MP1. Transient inhibition of its expression using RNA interference in fibroblasts resulted in decreased Rho activity and delayed cell spreading on fibronectin [7], and similar knockdown experiments in DU145 prostate cancer cells resulted in decreased migration on fibronectin [8]. The effect on migration was independent of MP1’s ability to activate ERK and PAK1, since the levels of phosphorylated ERK and PAK1 were unchanged upon MP1 knockdown. However, 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.Studies performed in conditional p14 knockout mice and in Drosophila have addressed the in vivo functions of MP1. The endosomal p14-MP1-MEK1 complex is required for cell