Local homologies of menin with tumor suppressor gene products and other proteins

Multiple endocrine neoplasia type 1 (MEN1) arises from the oncogenic transformation of neuroendocrine cells due to inactivating mutations of the MEN1 gene, a putative tumor-suppressor gene (tsg). Except for interaction with the proto-oncogene JunD, we have ignored the function of its product, menin, because no homology with other proteins was reported. Starting from our observation of clusters of basic amino acids, we show here that they fit motifs of both binding sites for heparin-analogs of the extracellular matrix (ECM) and nuclear localization signals, and that the motifs are conserved in known tsg. We also demonstrate that each tsg product has about four regions of scrambled homology with certain regions of menin. Such commonality of domains qualifies menin as a tsg. To provide more precise indications for the functions of menin, we probed the Non-Redundant GenBank database with the previously unnoticed tandemly repeated pentamer QSQGT/S (a motif that is always spared by MEN1-associated mutations), or with segments of the tsg-dissimilar sequences of menin. A single copy of the pentamer was found in a number of neuron proteins, two of which are of particular relevance: ankyrin 2 and neuroendocrine-dlg (NE-dlg). The tsg-dissimilar sequences matched only 6 proteins (or 0.0017% of the stored sequences): early nodulin GRP3 (fava bean), SphI restriction endonuclease (Streptomyces phaechromogenes), brain micro glutamic acid-rich protein, Alzheimer's protein precursor, syndecan 2 and talin. The homology with talin is extremely important because it concerns an E-cadherin motif that is also possessed by the product (ret) of the gene causative of another MEN syndrome, MEN2. This motif is spared by mutations in both MEN1 and MEN2. In conclusion, menin has the characteristics of a multiple-domain tsg and, thus, has multiple functions, such as inactivation of an AP1 transcription factor (the proto-oncogene JunD), regulation of the bioavailability of ECM-stored growth factors, anchoring of the integral proteins of the plasma membrane to the cytoskeleton and cell adhesion. The molecular link between MEN1 and MEN2 that we are describing should explain not only the similarities between the two MEN syndromes but also the occurrence of mixed syndromes.