Menin: a scaffold protein that controls gene expression and cell signaling

Abstract

The protein menin is encoded by the MEN1 gene, which is mutated in patients with multiple endocrine neoplasia type 1 (MEN1) syndrome. Although menin acts as a tumor suppressor in endocrine organs, it is required for leukemic transformation in mouse models. Menin possesses these dichotomous functions probably because it can both positively and negatively regulate gene expression, as well as interact with a multitude of proteins with diverse functions. Here, we review the recent progress in understanding the molecular mechanisms by which menin functions. The crystal structures of menin with different binding partners reveal that menin is a key scaffold protein that functionally crosstalks with various partners to regulate gene transcription and interplay with multiple signaling pathways.

Keywords: cell signaling; gene transcription; menin; scaffold protein.

Figure 1. Menin-interacting proteins and structures of menin with selected interacting proteins

(A) Four classes of menin interacting proteins based on their cellular functions in context of their interaction with menin: Transcription activators; transcription repressors; cell signaling proteins; and other proteins. Some menin interacting proteins can have dual roles as transcription factors and signaling molecules. (B) The surface representation of menin complexed with MLL1_MBM (menin binding motif of MLL1). (C) Overall ternary structure of menin complexed with MLL1_MBM-LBM (MLL1 menin binding motif- LEDGF binding motif) and LEDGF_IBM.( lens epithelium-derived growth factor integrase binding motif) (D) Crystal structure of menin in complex with JunD peptide. Menin interacts directly with JunD. Menin binding motif of JunD consists of residues 27–47.JunD_MBM is shown as purple stick model.(B–D) Reprinted by permission from [40].

Figure 2. Menin acts as a scaffold protein to tissue-specifically activate gene transcription

(A) In endocrine cells, menin recruits MLL1 to the promoters of cyclin dependent kinase (CDK) inhibitors p18 and p27. (B) In MLL-FP-induced leukemia cells c-Myb binds and recruits menin. Menin further recruits, via its central pocket, either wildtype MLL1 (green and violet) or MLL1-FPs, recruitment of MLL (wildtype containing MLL-N and MLL-C or MLL1-FP)can help recruit LEDGF and Dot1L. Menin can directly deposit H3K4me3, while Dot1L deposits H3K79 methylation, both leading to increased transcription of Hox genes, Meis1, and Ezh2, and blockade of myeloid differentiation. Depiction of c-Myb is not stoichiometric in this figure.

Figure 3. Menin represses gene expression via multiple mechanisms

(A) Menin interacts with JunD and recruits the Sin3A/histone deacetylase (HDAC) complex to reduce histone acetylation and suppress the expression of JunD targets such as Gastrin. The endogenous targets of JunD in this setting are unclear. (B) Menin also blocks JNK mediated phosphorylation of JunD, leading to repression of JunD transcriptional targets such as Gastrin. (C) In lung cancer cells, menin recruits EZH2 to the promoter of PTN to increase H3K27 trimethylation, a repressive mark, to downregulate the transcription of PTN. Whether menin directly interacts with EZH2 is yet to be determined (D) Menin can inhibit Hedgehog signaling by interacting with PRMT5 at the Gas1 promoter in pancreatic islets to increase PRMT5-mediated symmetric H4R3 dimethylation, which inhibits the expression of Gas1 and therefore Hedgehog signaling.

Figure 4. Menin regulates multiple signaling pathways

Menin interacts with SMAD3 or SMAD1/5 to enhance TGFβ or BMP signaling, respectively, in various types of cells. Menin also interacts with NFκB and recruits Sirt1 to deacetylate p65 to suppress NFκB-induced gene expression. β-catenin is located in cell membrane, in presence of Wnt signaling it is translocated to the nucleus. In insulinoma cells, menin interacts with β-catenin to upregulate gene transcription, whether they associate with each other at the promoter of Axin 2 is not known. In contrast in MEFs, menin promotes nuclear export of β-catenin to suppress its transcriptional activity. Menin also interacts with nuclear receptors such as ERα to promote expression their target genes. In the cytoplasm, inhibits receptor tyrosine kinase signaling through multiple mechanisms: inhibition of AKT, inhibition of SOS1-dependent activation of Ras, and suppression of ERK activation.