Menin and bone metabolism

Abstract

Menin, a product of the MEN1 gene, is related to the ontogeny of several cancers such as MEN1 and sporadic endocrine tumors, although it is considered to be a tumor suppressor. Many proteins interact with menin, and it is involved in various biological functions in several tissues. Menin plays some physiological and pathological roles related to transforming growth factor-beta (TGF-β) signaling pathway in the parathyroid, and it is implicated in the tumorigenesis of parathyroid tumors. In bone, the bone phenotype was observed in some menin-deleted mice. Menin is considered to support BMP-2- and Runx2-induced differentiation of mesenchymal cells into osteoblasts by interacting with Smad1/5, Runx2, β-catenin and LEF-1, although it has different effects on osteoblasts at later differentiation stages through TGF-β-Smad3 and AP-1 pathways. Further research is expected to shed more light on the role of menin in bone.

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

“…Consistent with this role, Men1 -null embryos display defects in cranial and facial development 29 . Menin is required for BMP-dependent multipotent mesenchymal stem cell commitment to the osteoblast lineage, and it facilitates this commitment through its interaction with the BMP effectors SMAD1/5 and their binding partner Runx2 31 .…”

“…Menin-interacting proteins can be classified into four main categories based on their cellular role in context to their association with menin: transcription activators, transcription repressors, and cell signaling proteins, and the other remaining interacting partners, which have diverse functions ranging from regulation of DNA repair to the structural integrity of the cell (Figure 1A). Menin-interacting transcriptional activators include transcription factors c-Myb, Protein-energy malnutrition (Pem) and runt-related transcription factor 2 (Runx2) 45 , 46, 29, 47 , and histone modifiers such as MLL1–2 (mixed lineage leukemia proteins) and histone H3 lysine 4 (H3K4) methyltransferases 48, 49 . The transcriptional repressors that directly or indirectly interact with menin include JunD, NFκB, homeobox HB9 Hlxb9 50 , 51 , 52 , histone deacetylases 1/2 (HDAC1/2), the histone deacetylase Sirt1, the histone H3 lysine 27 methyltransferase EZH2, and protein arginine methyltransferase 5 (PRMT5) 20, 53–55 .…”

“…The transcriptional repressors that directly or indirectly interact with menin include JunD, NFκB, homeobox HB9 Hlxb9 50 , 51 , 52 , histone deacetylases 1/2 (HDAC1/2), the histone deacetylase Sirt1, the histone H3 lysine 27 methyltransferase EZH2, and protein arginine methyltransferase 5 (PRMT5) 20, 53–55 . Notably, menin also interacts with multiple proteins that mediate several signaling pathways, such as the SMAD proteins, which transduce TGFβ signaling 29, 56 ; β-catenin, a member of the Wnt signaling pathway 57–60 ; nuclear receptors such as estrogen receptor and PPARγ; and Ras-activating protein SOS1 19, 61, 62 . The physiological and genetic impact of the interaction between menin and many of its interacting proteins in model organisms remains to be explored.…”

“…Menin also regulates BMP signaling, which is critical for bone development 29 . Consistent with this role, Men1 -null embryos display defects in cranial and facial development 29 .…”

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“…It plays physiological and pathological roles related to transforming growth factor-beta (TGF-β) signaling pathway in the parathyroid. Menin supports BMP-2-and Runx2-induced differentiation of mesenchymal cells into osteoblasts by interacting with Smad1/5, Runx2, β-catenin and LEF-1, although it has different effects on osteoblasts at later differentiation stages through TGF-β-Smad3 and AP-1 pathways [61]. Silk fibroin (SF) is used in osteoregenerative therapy.…”