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Menin interacts with IQGAP1 to enhance intercellular adhesion of β-cells

Abstract

Multiple endocrine neoplasia type 1 (MEN1) is a dominantly inherited tumor syndrome that results from the mutation of the MEN1 gene that encodes protein menin. Stable overexpression of MEN1 has been shown to partially suppress the Ras-mediated morphological changes of fibroblast cells. Little is known about the molecular mechanisms by which menin decreases the oncogenic effects on cell morphology and other phenotypes. Here we showed that ectopic expression of menin in pretumor β-cells increases islet cell adhesion and reduces cell migration. Our further studies revealed that menin interacts with the scaffold protein, IQ motif containing GTPase activating protein 1 (IQGAP1), reduces GTP–Rac1 interaction with IQGAP1 but increases epithelial cadherin (E-cadherin)/β-catenin interaction with IQGAP1. Consistent with an essential role for menin in regulating β-cell adhesion in vivo, accumulations of β-catenin and E-cadherin are reduced at cell junctions in the islets from Men1-excised mice. Together, these results define a novel menin–IQGAP1 pathway that controls cell migration and cell–cell adhesion in endocrine cells.

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Acknowledgements

The parent clonal βHC9 insulin-secreting cells (Radvanyi et al., 1993) were obtained from the cell repository of the Diabetes Research Center at the University of Pennsylvania, with permission of Dr FM Matschinsky. We thank Dr Faming Zhang for his gifts of purified MBP-tagged menin and nontagged menin, Dr Martin A Schwartz for mutant human Rac1 vectors and Dr Ruth Kroschewski for the IQGAP1 C-terminal constructs (C1–C4). All confocal images and quantitative analyses of fluorescent intensity were conducted at the Biomedical Imaging Core Facility at the University of Pennsylvania. We thank Peter Blessington, Alicia Nelson, Hai Shen, Mercy Gohil and Elena Blagoi for their technical assistance. A special thanks to Dr Claudia Andl and Dr Margaret Chou for their stimulating discussions. This work was supported in part from NIH grants (R01-CA-100912 and R01-CA-113962 to XH, and R01- NS051746 to GSB), and a grant from the American Diabetes Association (7-07-RA-60 to XH).

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Correspondence to X Hua.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Yan, J., Yang, Y., Zhang, H. et al. Menin interacts with IQGAP1 to enhance intercellular adhesion of β-cells. Oncogene 28, 973–982 (2009). https://doi.org/10.1038/onc.2008.435

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