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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References
Andl CD, Fargnoli BB, Okawa T, Bowser M, Takaoka M, Nakagawa H et al. (2006). Coordinated functions of E-cadherin and transforming growth factor beta receptor II in vitro and in vivo. Cancer Res 66: 9878–9885.
Bai F, Pei XH, Nishikawa T, Smith MD, Xiong Y . (2007). p18Ink4c, but not p27Kip1, collaborates with Men1 to suppress neuroendocrine organ tumors. Mol Cell Biol 27: 1495–1504.
Bashour AM, Fullerton AT, Hart MJ, Bloom GS . (1997). IQGAP1, a Rac- and Cdc42-binding protein, directly binds and cross-links microfilaments. J Cell Biol 137: 1555–1566.
Bensenor LB, Kan HM, Wang N, Wallrabe H, Davidson LA, Cai Y et al. (2007). IQGAP1 regulates cell motility by linking growth factor signaling to actin assembly. J Cell Sci 120: 658–669.
Bertolino P, Tong WM, Herrera PL, Casse H, Zhang CX, Wang ZQ . (2003). Pancreatic beta-cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice. Cancer Res 63: 4836–4841.
Brandt DT, Marion S, Griffiths G, Watanabe T, Kaibuchi K, Grosse R . (2007). Dia1 and IQGAP1 interact in cell migration and phagocytic cup formation. J Cell Biol 178: 193–200.
Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR et al. (1997). Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276: 404–407.
Chen YX, Yan J, Keeshan K, Tubbs AT, Wang H, Silva A et al. (2006). The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression. Proc Natl Acad Sci USA 103: 1018–1023.
Crabtree JS, Scacheri PC, Ward JM, Garrett-Beal L, Emmert-Buck MR, Edgemon KA et al. (2001). A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. Proc Natl Acad Sci USA 98: 1118–1123.
Crabtree JS, Scacheri PC, Ward JM, McNally SR, Swain GP, Montagna C et al. (2003). Of mice and MEN1: insulinomas in a conditional mouse knockout. Mol Cell Biol 23: 6075–6085.
Donnadieu E, Cefai D, Tan YP, Paresys G, Bismuth G, Trautmann A . (1992). Imaging early steps of human T cell activation by antigen-presenting cells. J Immunol 148: 2643–2653.
Fukata M, Kuroda S, Nakagawa M, Kawajiri A, Itoh N, Shoji I et al. (1999). Cdc42 and Rac1 regulate the interaction of IQGAP1 with beta-catenin. J Biol Chem 274: 26044–26050.
Fukata M, Nakagawa M, Itoh N, Kawajiri A, Yamaga M, Kuroda S et al. (2001). Involvement of IQGAP1, an effector of Rac1 and Cdc42 GTPases, in cell–cell dissociation during cell scattering. Mol Cell Biol 21: 2165–2183.
Fukata M, Watanabe T, Noritake J, Nakagawa M, Yamaga M, Kuroda S et al. (2002). Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170. Cell 109: 873–885.
Grohmanova K, Schlaepfer D, Hess D, Gutierrez P, Beck M, Kroschewski R . (2004). Phosphorylation of IQGAP1 modulates its binding to Cdc42, revealing a new type of rho-GTPase regulator. J Biol Chem 279: 48495–48504.
Guru SC, Crabtree JS, Brown KD, Dunn KJ, Manickam P, Prasad NB et al. (1999). Isolation, genomic organization, and expression analysis of Men1, the murine homolog of the MEN1 gene. Mamm Genome 10: 592–596.
Guru SC, Goldsmith PK, Burns AL, Marx SJ, Spiegel AM, Collins FS et al. (1998). Menin, the product of the MEN1 gene, is a nuclear protein. Proc Natl Acad Sci USA 95: 1630–1634.
Hart MJ, Callow MG, Souza B, Polakis P . (1996). IQGAP1, a calmodulin-binding protein with a rasGAP-related domain, is a potential effector for cdc42Hs. EMBO J 15: 2997–3005.
Huang SC, Zhuang Z, Weil RJ, Pack S, Wang C, Krutzsch HC et al. (1999). Nuclear/cytoplasmic localization of the multiple endocrine neoplasia type 1 gene product, menin. Lab Invest 79: 301–310.
Hughes CM, Rozenblatt-Rosen O, Milne TA, Copeland TD, Levine SS, Lee JC et al. (2004). Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell 13: 587–597.
Jiang K, Sun J, Cheng J, Djeu JY, Wei S, Sebti S . (2004). Akt mediates Ras downregulation of RhoB, a suppressor of transformation, invasion, and metastasis. Mol Cell Biol 24: 5565–5576.
Kim YS, Burns AL, Goldsmith PK, Heppner C, Park SY, Chandrasekharappa SC et al. (1999). Stable overexpression of MEN1 suppresses tumorigenicity of RAS. Oncogene 18: 5936–5942.
Kissil JL, Walmsley MJ, Hanlon L, Haigis KM, Bender Kim CF, Sweet-Cordero A et al. (2007). Requirement for Rac1 in a K-ras induced lung cancer in the mouse. Cancer Res 67: 8089–8094.
Kuroda S, Fukata M, Nakagawa M, Fujii K, Nakamura T, Ookubo T et al. (1998). Role of IQGAP1, a target of the small GTPases Cdc42 and Rac1, in regulation of E-cadherin-mediated cell–cell adhesion. Science 281: 832–835.
La P, Schnepp RW, Petersen CD, Silva AC, Hua X . (2004). Tumor suppressor menin regulates expression of insulin-like growth factor binding protein 2. Endocrinology 145: 3443–3450.
Lakhani VT, You YN, Wells SA . (2007). The multiple endocrine neoplasia syndromes. Annu Rev Med 58: 253–265.
Lambert M, Choquet D, Mege RM . (2002). Dynamics of ligand-induced, Rac1-dependent anchoring of cadherins to the actin cytoskeleton. J Cell Biol 157: 469–479.
Le Clainche C, Schlaepfer D, Ferrari A, Klingauf M, Grohmanova K, Veligodskiy A et al. (2007). IQGAP1 stimulates actin assembly through the N-WASP-Arp2/3 pathway. J Biol Chem 282: 426–435.
Li S, Wang Q, Chakladar A, Bronson RT, Bernards A . (2000). Gastric hyperplasia in mice lacking the putative Cdc42 effector IQGAP1. Mol Cell Biol 20: 697–701.
Lopez-Egido J, Cunningham J, Berg M, Oberg K, Bongcam-Rudloff E, Gobl A . (2002). Menin's interaction with glial fibrillary acidic protein and vimentin suggests a role for the intermediate filament network in regulating menin activity. Exp Cell Res 278: 175–183.
Mataraza JM, Briggs MW, Li Z, Entwistle A, Ridley AJ, Sacks DB . (2003). IQGAP1 promotes cell motility and invasion. J Biol Chem 278: 41237–41245.
Mataraza JM, Li Z, Jeong HW, Brown MD, Sacks DB . (2007). Multiple proteins mediate IQGAP1-stimulated cell migration. Cell Signal 19: 1857–1865.
Mateer SC, McDaniel AE, Nicolas V, Habermacher GM, Lin MJ, Cromer DA et al. (2002). The mechanism for regulation of the F-actin binding activity of IQGAP1 by calcium/calmodulin. J Biol Chem 277: 12324–12333.
Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, Allis CD et al. (2002). MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell 10: 1107–1117.
Milne TA, Hughes CM, Lloyd R, Yang Z, Rozenblatt-Rosen O, Dou Y et al. (2005). Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc Natl Acad Sci USA 102: 749–754.
Noritake J, Watanabe T, Sato K, Wang S, Kaibuchi K . (2005). IQGAP1: a key regulator of adhesion and migration. J Cell Sci 118: 2085–2092.
Price LS, Hajdo-Milasinovic A, Zhao J, Zwartkruis FJ, Collard JG, Bos JL . (2004). Rap1 regulates E-cadherin-mediated cell–cell adhesion. J Biol Chem 279: 35127–35132.
Radvanyi F, Christgau S, Baekkeskov S, Jolicoeur C, Hanahan D . (1993). Pancreatic beta cells cultured from individual preneoplastic foci in a multistage tumorigenesis pathway: a potentially general technique for isolating physiologically representative cell lines. Mol Cell Biol 13: 4223–4232.
Ridley AJ . (2001). Rho family proteins: coordinating cell responses. Trends Cell Biol 11: 471–477.
Rittmeyer EN, Daniel S, Hsu SC, Osman MA . (2008). A dual role for IQGAP1 in regulating exocytosis. J Cell Sci 121: 391–403.
Schnepp RW, Chen YX, Wang H, Cash T, Silva A, Diehl JA et al. (2006). Mutation of tumor suppressor gene Men1 acutely enhances proliferation of pancreatic islet cells. Cancer Res 66: 5707–5715.
Shaner NC, Campbell RE, Steinbach PA, Giepmans BN, Palmer AE, Tsien RY . (2004). Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein. Nat Biotechnol 22: 1567–1572.
Taylor SJ, Shalloway D . (1996). Cell cycle-dependent activation of Ras. Curr Biol 6: 1621–1627.
Watanabe T, Noritake J, Kaibuchi K . (2005). Roles of IQGAP1 in cell polarization and migration. Novartis Found Symp 269: 92–101; discussion 101–105, 223–230.
Watanabe T, Wang S, Noritake J, Sato K, Fukata M, Takefuji M et al. (2004). Interaction with IQGAP1 links APC to Rac1, Cdc42, and actin filaments during cell polarization and migration. Dev Cell 7: 871–883.
Yan J, Chen YX, Desmond A, Silva A, Yang Y, Wang H et al. (2006a). Cdx4 and menin co-regulate hoxa9 expression in hematopoietic cells. PLoS ONE 1: e47.
Yan J, Xu L, Crawford G, Wang Z, Burgess SM . (2006b). The forkhead transcription factor FoxI1 remains bound to condensed mitotic chromosomes and stably remodels chromatin structure. Mol Cell Biol 26: 155–168.
Yokoyama A, Somervaille TC, Smith KS, Rozenblatt-Rosen O, Meyerson M, Cleary ML . (2005). The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell 123: 207–218.
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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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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DOI: https://doi.org/10.1038/onc.2008.435
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