Cyclin-dependent kinase-mediated phosphorylation of breast cancer metastasis suppressor 1 (BRMS1) affects cell migration

Abstract

Expression of Breast Cancer Metastasis Suppressor 1 (BRMS1) reduces the incidence of metastasis in many human cancers, without affecting tumorigenesis. BRMS1 carries out this function through several mechanisms, including regulation of gene expression by binding to the mSin3/histone deacetylase (HDAC) transcriptional repressor complex. In the present study, we show that BRMS1 is a novel substrate of Cyclin-Dependent Kinase 2 (CDK2) that is phosphorylated on serine 237 (S237). Although CDKs are known to regulate cell cycle progression, the mutation of BRMS1 on serine 237 did not affect cell cycle progression and proliferation of MDA-MB-231 breast cancer cells; however, their migration was affected. Phosphorylation of BRMS1 does not affect its association with the mSin3/HDAC transcriptional repressor complex or its transcriptional repressor activity. The serine 237 phosphorylation site is immediately proximal to a C-terminal nuclear localization sequence that plays an important role in BRMS1-mediated metastasis suppression but phosphorylation does not control BRMS1 subcellular localization. Our studies demonstrate that CDK-mediated phosphorylation of BRMS1 regulates the migration of tumor cells.

Cdk2 regulates metastasis suppressor BRMS1

“…6 There are still open questions about how S237 phosphorylation alters the function of BRMS1, as mutation of this site does not affect BRMS1 localization, binding to the HDAC complex or RBP1 protein, or the transcriptional regulation of osteopontin by BRMS1. 3 As observed by the authors, the S237 site is immediately proximate to the site of an NLS2 putative nuclear localization signal which is known to be important to the ability of BRMS1 to suppress metastasis, and this bears further investigation. More recently, it has been found that BRMS1 acts as a ubiquitin ligase toward the p300 histone acetyltransferase where alteration of this ubiquitin ligase activity increases metastasis, 7 and this is another possible function of BRMS1 that may be modulated by S237 phosphorylation.…”

“…Consistent with our current knowledge of BRMS1 as a metastasis suppressor that does not influence primary tumor growth, Roesley et al also show that overexpression of BRMS1 S237D (which mimics the constitutively phosphorylated protein) did not suppress the proliferation or colony forming potential of cancer cells. 3 This is an important finding as it suggests that high CDK2 activity may suppress invasion and metastasis via BRMS1, though paradoxically high CDK2 activity is normally assumed to be tumorigenic. However, since the initiation of a primary tumor and metastasis are distinct processes, it is not surprising that multifunctional master regulators such as cyclins and CDKs can play different roles in these disease stages, resulting in temporal changes to their expression as disease progresses.…”

“…For the most part the functional consequence of these interactions and phosphorylations has not been characterized, though recent work has shown novel functions for CDK1 and CDK2 in epigenetic regulation and the non-cell cycle CDK, CDK5, in neuronal function including synaptic vesicle trafficking. 2 Roesley et al 3 have now identified a novel link between CDK2 and cell migration by characterizing the CDK2-mediated phosphorylation of BRMS1. BRMS1 (or breast cancer metastasis suppressor 1) associates with histone deactylase complexes that remodel chromatin, as well as acting as a transcriptional repressor.…”

Profile of palbociclib in the treatment of metastatic breast cancer

“…Rb protein acts as a tumor suppressor controlling G1/S transition of cell cycle. 27 When Rb is phosphorylated, it loses its negative control on G1/S transition. 28 Hence, activating E2F family of transcription factors that allows DNA replication to start.…”

BRMS1 participates in regulating cell sensitivity to DNA interstrand crosslink damage by interacting with FANCI

“…Breast cancer metastasis suppressor 1 (BRMS1) was first discovered for its significant inhibition of metastasis in breast cancer cells (1). Depending on the cell types used, BRMS1 has been noted to inhibit multiple steps in the invasion-metastasis cascade, including cell communication (2,3), cell migration (4,5), cell apoptosis (6,7), epithelial-mesenchymal transition (EMT) (8), among others. Several important BRMS1-interacting proteins have been identified, providing possible clues to the molecular mechanisms of action of BRMS1.…”