Perturbation of BRMS1 interactome reveals pathways that impact cell migration

Breast Cancer Metastasis Suppressor 1 (BRMS1) expression has been associated with longer patient survival in multiple cancer types. Understanding BRMS1 at the protein level will provide insights into both mechanism of action and enhance potential therapeutic development. We previously mapped the C-terminus of BRMS1 as critical for metastasis suppression and hypothesized that critical protein interactions in this region will explain function. These studies indicate that phosphorylation status at S237 regulates BRMS1 interactions related to a variety of biological processes, phenotypes [cell cycle (e.g., CDKN2A), DNA repair (e.g., BRCA1)], and metastasis [(e.g., TCF2 and POLE2)]. Presence of the C-terminal site appears to be critical for BRMS1 directed metastasis suppression, as demonstrated by in vitro migration assays. These assays demonstrated that presence of S237 directly decreased MDA-MB-231 migration. This study furthers our understanding of BRMS1s molecular role, as it demonstrates that BRMS1 C-terminus is involved in direct protein-protein interactions. Several of the interacting proteins are associated with cancer and metastasis, which may result in metastasis suppression as suggested by in vitro findings. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/429764v1_ufig3.gif" ALT="Figure 3"> View larger version (18K): org.highwire.dtl.DTLVardef@17c0662org.highwire.dtl.DTLVardef@18738cdorg.highwire.dtl.DTLVardef@a222b1org.highwire.dtl.DTLVardef@93cf50_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract Utilizing BRMS1 mutants to mimic-phosphorylation, this study demonstrates that S237-phosphorylation disrupts BRMS1 protein-protein interactions. The disruption includes both known Sin3/HDAC interactors as well as additionally previously unidentified Sin3-indepedent binding partners (indicated by increased opacity). It is revealed that BRMS1-phosphorylation status also more greatly inhibits cell migration (indicated by +) compared to the unphosphorylated state, suggesting that phosphorylation plays a role in BRMS1 metastatsis suppresion function, potentially though altered protein interactions. C_FIG