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| At least 10 alternate protein isoforms of Bin1 are expressed in different tissues. Isoforms 9 and 10 are ubiquitous. Isoform 8 is muscle-specific. Isoforms 1-7 are expressed predominantly in the central nervous system. Two tumor-specific isoforms include an exon termed 12A that is normally spliced into Bin1 mRNA only with other exons expressed in the central nervous system. These tumor-specific isoforms occur commonly in cancer and they represent loss of function with regard to tumor suppression activity and nuclear localization capability. BAR, BAR domain; SH3, SH3 domain; MBD, Myc binding domain; CLAP, clathrin-associated protein binding region; PI, phosphoinositide binding region. Exons are numbered by reference to Wechsler-Reya et al. (1997). |
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Description | Bin1 contains N-terminal BAR (Bin1/Amphihysin/Rvs) domain with predicted coiled-coil structure and a C-terminal SH3 domain (Sakamuro et al., 1996). Bin1 encodes proteins of 409 to 593 amino acids; isoform 1 (593 aa), isoform 2 (550 aa), isoform 3 (506 aa), isoform 4 (497 aa), isoform 5 (518 aa), isoform 6 (482 aa), isoform 7 (475 aa), isoform 8 (454 aa), isoform 9 (439 aa), and isoform 10 (409 aa). Isoform 10 is the smallest and isoform 1 is the largest in size. Also, Bin1 has predicted molecular weight of 45432 to 64568 Da; isoform 1 (64568 Da), isoform 2 (59806 Da), isoform 3 (55044 Da), isoform 4 (54817 Da), isoform 5 (56368 Da), isoform 6 (52889 Da), isoform 7 (51606 Da), isoform 8 (50054 Da), isoform 9 (48127 Da), and isoform 10 (45432 Da). Isoforms 9 and 10 are ubiquitous in expression. Isoform 8 is expressed specifically in skeletal muscle. Isoforms 1-7 are expressed predominantly in the central nervous system. These 10 different splice isoforms differ widely in subcellular localization, tissue distribution, and ascribed functions, with isoforms 1-7 predominantly cytosolic but isoforms 8-10 found in both the nucleus and/or cytosol of certain cell types (Sakamuro et al., 1996; Muller et al., 2003). Recent studies demonstrated that the coiled-coil BIN1 BAR peptide encodes a novel BIN1 MID domain, through which BIN1 acts as a MYC-independent cancer suppressor (Lundgaard et al., 2011). |
Expression | Bin1 is widely expressed (Wechsler-Reya et al., 1997; Chapuis et al., 2013). Patterns of isoform expression are noted above in the diagram legend. |
Localisation | Bin1 is localized both in nuclear and cytosolic in the cerebral cortex and cerebellum of brain. Bin1 is localized mainly in nuclear in bone marrow cells whereas it is localized mainly in cytosolic in peripheral lymphoid cells. Bin1 is nuclear or nucleocytosolic in basal cells of skin, breast, or prostate, whereas it is cytosolic or plasma membrane localized in gastrointestinal cells (DuHadaway et al., 2003). In cardiac muscles Bin1 generate T-tubules and also designates T-tubules as the appropriate site for delivery of L-type calcium channels (Hong et al., 2010). |
Function | Bin1 encodes members of the BAR (Bin/Amphiphysin/Rvs) adapter family which have been implicated in membrane dynamics, such as vesicle fusion and trafficking, specialized membrane organization, actin organization, cell polarity, stress signaling, transcription, immunomodulation and tumor suppression. BAR adapter proteins are now recognized to be part of a larger superfamily of structurally related proteins that includes the so-called F-BAR and I-BAR adapter proteins (Ren et al., 2006; Prendergast et al., 2009). Membrane binding and tubulation: The Bin1 BAR domain can mediate binding and tubulation of curved membranes (Lee et al., 2002; Wu et al., 2014). Crystal structures of the BAR domains from human BIN1 and its fruit fly homolog reveal a dimeric banana-shaped 6-alpha-helix bundle that can nestle against the charged head groups on a curved lipid bilayer. Structural studies implicate specific alpha-helices in tubulation activity. Biochemical analyses implicate Bin1 in vesicle fission and fusion processes, with the SH3 domain providing an essential contribution to these processes through the recruitment of dynamins (Ren et al., 2006). Vesicle trafficking: Bin1 is implicated in endocytosis and intracellular endosome traffic through interactions with Rab5 guanine nucleotide exchange factors (Rab GEFs) and the sorting nexin protein Snx4. Complexes of neuronal Amph-I with neuron-specific isoforms of Bin1 (Amph-II) have been implicated in synaptic vesicle recycling in the brain. Genetic studies of the Bin1 homolog in budding yeast indicate an essential role in endocytosis, however, this role appears to be non-essential for homologs in fission yeast, fruit flies, and mice (Leprince et al., 2003). Cell polarity: Genetic analyses of the Bin1 homologs in yeast and fruit flies suggest a integrative function in cell polarity, possibly mediated by effects on actin organization and vesicle trafficking. In budding yeast, the Bin1 homolog RVS167 lies at a central nodal point for integrating cell polarity signaling (Balguerie et al., 1999). Genetic ablation of the Bin1 homolog in fruit flies causes mislocalization of the cell polarity complex Dlg/Scr/Lgl, normally localized to the tight junction, that is implicated in epithelial polarity and suppression of tumor-like growths in flies (Humbert et al., 2003). Transcription: Ubiquitous and muscle-specific isoforms of Bin1 that can localize to the nucleus can bind to c-Myc and suppress its transcriptional transactivation activity (Elliott et al., 1999). Tethering the BAR domain of Bin1 to DNA is sufficient to repress transcription. Genetic studies in fission yeast demonstrate that the functional homolog hob1+ is essential to silence transcription of heterochromatin at telomeric and centromeric chromosomal loci by supporting a Rad6-Set1 pathway of transcriptional repression (Ramalingam and Prendergast, 2007). Muscle function: Mutations of the human BIN1 gene are associated with centronuclear myopathy, a disorder marked by severe muscle weakness (Nicot et al., 2007; Wu et al., 2014). In skeletal muscle, Bin1 localizes to T tubules where it appears to support ion flux (Lee et al., 2002; Butler et al., 1997). In vitro studies of terminal muscle differentiation implicate Bin1 in myoblast cell cycle arrest and fusion during tubule formation (Wechsler-Reya et al., 1998). Cardiac function: Mouse genetic studies indicate that Bin1 is required for cardiac development (Hong et al., 2010). Bin1 levels decreases in failing hearts and low level of plasma Bin1 correlates with heart failure and predicts arrhythmia in patients with arrhythmogenic right ventricular cardiomyopathy (Hong et al., 2012). Cognition and Memory: Bin1 is one of the candidate genes involved in Alzheimer's disease. Bin1 is the most important risk locus for late onset Alzheimer's disease. Bin1 affects AD risk primarily by modulating tau pathology (Tan et al., 2013; Kingwell, 2013; Chapius et al., 2013). Immunomodulation and Barrier Function: Bin1 is a genetic modifier of experimental colitis that controls the paracellular pathway of transcellular ion transport regulated by cellular tight junctions (Chang et al., 2012). Apoptosis and Senescence: Bin1 is crucial for the function of default pathways of classical apoptosis or senescence triggered by the Myc or Raf oncogenes in primary cells (Prendergast et al., 2009). In human tumor cells, enforced expression of Bin1 triggers a non-classical program of cell death that is caspase independent and associated with activation of serine proteases (Elliott et al., 2000). Tumor suppression: Attenuation of Bin1 function by silencing or missplicing is a frequent event in multiple human cancers including breast, prostate, skin, lung, and colon cancers (Sakamuro et al., 1996; Ge et al., 2000b). In breast cancer, attenuated expression of Bin1 is associated with increased metastasis and poor clinical outcome (Chang et al., 2007b). In human tumor cells, ectopic expression of ubiquitous or muscle Bin1 isoforms causes growth arrest or caspase-independent cell death (Prendergast et al., 2009). A Bin1 missplicing event that occurs frequently in human cancers is sufficient to extinguish these activities. In primary rodent cells, Bin1 inhibits oncogenic co-transformation by Myc, adenovirus E1A, or mutant p53 but not SV40 T antigen (Elliott et al., 1999; Elliott et al., 2000). Mouse genetic studies establish that loss of Bin1 causes lung and liver cancers during aging (Chang et al., 2007a). In mice where breast or colon tumors are initiated by carcinogen treatment, Bin1 deletion causes progression to more aggressive malignant states (Chang et al., 2007b). Oncogenically transformed cells lacking Bin1 exhibit reduced susceptibility to apoptosis and increased proliferation, invasion, immune escape, and tumor formation (Muller et al., 2004, Muller et al., 2005). Activation of metalloproteinase MMP9 and immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) have been implicated respectively in invasion and immune escape caused by Bin1 loss (Chang et al., 2007b). Cisplatin is the most important and efficacious chemotherapeutic agent for the treatment of advanced gastric cancer. The oncoprotein c-Myc suppresses bridging integrator 1 (BIN1), thereby releasing poly(ADP-ribose)polymerase 1, which results in increased DNA repair activity and allows cancer cells to acquire cisplatin resistance (Tanida et al., 2012). Null phenotype in mouse: Bin1 knockout mice are perinatal lethal owing to myocardial hypertrophy where myofibrils of ventricular cardiomyocytes are severely disorganized (Muller et al., 2003). Genetic mosaic mice display increased susceptibility to inflammation, premalignant lesions in prostate and pancreas, and formation of liver and lung carcinoma. Female mosaic mice exhibit increased fecundity during aging. Tissue-specific gene ablation in skin or breast facilitates carcinogenesis (Chang et al., 2007a). |
Homology | The longest Bin1 alternate splice variant in human brain exhibits 71% amino acid sequences similarity and 55% amino acid sequence identity with amphiphysin-I (amph-I) (Ren et al., 2006). Bin1 is also closely related to the mammalian amphiphysin-like genes Bin2 and Bin3 (Routhier et al., 2003). Genetic homologs of Bin1 that exist in budding and fission yeast (RVS167 and hob1+) and in fruit flies (amphiphysin) are well-characterized (Ren et al., 2006; Prendergast et al., 2009). |
Rvs167p, the budding yeast homolog of amphiphysin, colocalizes with actin patches. |
Balguerie A, Sivadon P, Bonneu M, Aigle M. |
J Cell Sci. 1999 Aug;112 ( Pt 15):2529-37. |
PMID 10393809 |
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Amphiphysin II (SH3P9; BIN1), a member of the amphiphysin/Rvs family, is concentrated in the cortical cytomatrix of axon initial segments and nodes of ranvier in brain and around T tubules in skeletal muscle. |
Butler MH, David C, Ochoa GC, Freyberg Z, Daniell L, Grabs D, Cremona O, De Camilli P. |
J Cell Biol. 1997 Jun 16;137(6):1355-67. |
PMID 9182667 |
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Bin1 attenuation suppresses experimental colitis by enforcing intestinal barrier function. |
Chang MY, Boulden J, Valenzano MC, Soler AP, Muller AJ, Mullin JM, Prendergast GC. |
Dig Dis Sci. 2012 Jul;57(7):1813-21. doi: 10.1007/s10620-012-2147-y. Epub 2012 Apr 18. |
PMID 22526583 |
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Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. |
Chapuis J, Hansmannel F, Gistelinck M, Mounier A, Van Cauwenberghe C, Kolen KV, Geller F, Sottejeau Y, Harold D, Dourlen P, Grenier-Boley B, Kamatani Y, Delepine B, Demiautte F, Zelenika D, Zommer N, Hamdane M, Bellenguez C, Dartigues JF, Hauw JJ, Letronne F, Ayral AM, Sleegers K, Schellens A, Broeck LV, Engelborghs S, De Deyn PP, Vandenberghe R, O'Donovan M, Owen M, Epelbaum J, Mercken M, Karran E, Bantscheff M, Drewes G, Joberty G, Campion D, Octave JN, Berr C, Lathrop M, Callaerts P, Mann D, Williams J, Buee L, Dewachter I, Van Broeckhoven C, Amouyel P, Moechars D, Dermaut B, Lambert JC; GERAD consortium. |
Mol Psychiatry. 2013 Nov;18(11):1225-34. doi: 10.1038/mp.2013.1. Epub 2013 Feb 12. |
PMID 23399914 |
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Immunohistochemical analysis of Bin1/Amphiphysin II in human tissues: diverse sites of nuclear expression and losses in prostate cancer. |
DuHadaway JB, Lynch FJ, Brisbay S, Bueso-Ramos C, Troncoso P, McDonnell T, Prendergast GC. |
J Cell Biochem. 2003 Feb 15;88(3):635-42. |
PMID 12532338 |
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The c-Myc-interacting adaptor protein Bin1 activates a caspase-independent cell death program. |
Elliott K, Ge K, Du W, Prendergast GC. |
Oncogene. 2000 Sep 28;19(41):4669-84. |
PMID 11032017 |
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Bin1 functionally interacts with Myc and inhibits cell proliferation via multiple mechanisms. |
Elliott K, Sakamuro D, Basu A, Du W, Wunner W, Staller P, Gaubatz S, Zhang H, Prochownik E, Eilers M, Prendergast GC. |
Oncogene. 1999 Jun 17;18(24):3564-73. |
PMID 10380878 |
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Mechanism for elimination of a tumor suppressor: aberrant splicing of a brain-specific exon causes loss of function of Bin1 in melanoma. |
Ge K, DuHadaway J, Du W, Herlyn M, Rodeck U, Prendergast GC. |
Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9689-94. |
PMID 10449755 |
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Losses of the tumor suppressor BIN1 in breast carcinoma are frequent and reflect deficits in programmed cell death capacity. |
Ge K, Duhadaway J, Sakamuro D, Wechsler-Reya R, Reynolds C, Prendergast GC. |
Int J Cancer. 2000a Feb 1;85(3):376-83. |
PMID 10652430 |
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Loss of heterozygosity and tumor suppressor activity of Bin1 in prostate carcinoma. |
Ge K, Minhas F, Duhadaway J, Mao NC, Wilson D, Buccafusca R, Sakamuro D, Nelson P, Malkowicz SB, Tomaszewski J, Prendergast GC. |
Int J Cancer. 2000b Apr 15;86(2):155-61. |
PMID 10738240 |
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BIN1 inhibits colony formation and induces apoptosis in neuroblastoma cell lines with MYCN amplification. |
Hogarty MD, Liu X, Thompson PM, White PS, Sulman EP, Maris JM, Brodeur GM. |
Med Pediatr Oncol. 2000 Dec;35(6):559-62. |
PMID 11107117 |
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Plasma BIN1 correlates with heart failure and predicts arrhythmia in patients with arrhythmogenic right ventricular cardiomyopathy. |
Hong TT, Cogswell R, James CA, Kang G, Pullinger CR, Malloy MJ, Kane JP, Wojciak J, Calkins H, Scheinman MM, Tseng ZH, Ganz P, De Marco T, Judge DP, Shaw RM. |
Heart Rhythm. 2012 Jun;9(6):961-7. doi: 10.1016/j.hrthm.2012.01.024. Epub 2012 Jan 31. |
PMID 22300662 |
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BIN1 localizes the L-type calcium channel to cardiac T-tubules. |
Hong TT, Smyth JW, Gao D, Chu KY, Vogan JM, Fong TS, Jensen BC, Colecraft HM, Shaw RM. |
PLoS Biol. 2010 Feb 16;8(2):e1000312. doi: 10.1371/journal.pbio.1000312. |
PMID 20169111 |
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Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer. |
Humbert P, Russell S, Richardson H. |
Bioessays. 2003 Jun;25(6):542-53. (REVIEW) |
PMID 12766944 |
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Investigation of a family with autosomal dominant dilated cardiomyopathy defines a novel locus on chromosome 2q14-q22. |
Jung M, Poepping I, Perrot A, Ellmer AE, Wienker TF, Dietz R, Reis A, Osterziel KJ. |
Am J Hum Genet. 1999 Oct;65(4):1068-77. |
PMID 10486326 |
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Alzheimer disease: BIN1 variant increases risk of Alzheimer disease through tau. |
Kingwell K. |
Nat Rev Neurol. 2013 Apr;9(4):184. doi: 10.1038/nrneurol.2013.34. Epub 2013 Mar 5. |
PMID 23458971 |
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Methylation of the BIN1 gene promoter CpG island associated with breast and prostate cancer. |
Kuznetsova EB, Kekeeva TV, Larin SS, Zemlyakova VV, Khomyakova AV, Babenko OV, Nemtsova MV, Zaletayev DV, Strelnikov VV. |
J Carcinog. 2007 May 4;6:9. |
PMID 17477881 |
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Amphiphysin 2 (Bin1) and T-tubule biogenesis in muscle. |
Lee E, Marcucci M, Daniell L, Pypaert M, Weisz OA, Ochoa GC, Farsad K, Wenk MR, De Camilli P. |
Science. 2002 Aug 16;297(5584):1193-6. |
PMID 12183633 |
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Sorting nexin 4 and amphiphysin 2, a new partnership between endocytosis and intracellular trafficking. |
Leprince C, Le Scolan E, Meunier B, Fraisier V, Brandon N, De Gunzburg J, Camonis J. |
J Cell Sci. 2003 May 15;116(Pt 10):1937-48. Epub 2003 Mar 26. |
PMID 12668730 |
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Identification of a novel effector domain of BIN1 for cancer suppression. |
Lundgaard GL, Daniels NE, Pyndiah S, Cassimere EK, Ahmed KM, Rodrigue A, Kihara D, Post CB, Sakamuro D. |
J Cell Biochem. 2011 Oct;112(10):2992-3001. doi: 10.1002/jcb.23222. |
PMID 21678469 |
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Targeted disruption of the murine Bin1/Amphiphysin II gene does not disable endocytosis but results in embryonic cardiomyopathy with aberrant myofibril formation. |
Muller AJ, Baker JF, DuHadaway JB, Ge K, Farmer G, Donover PS, Meade R, Reid C, Grzanna R, Roach AH, Shah N, Soler AP, Prendergast GC. |
Mol Cell Biol. 2003 Jun;23(12):4295-306. |
PMID 12773571 |
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Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. |
Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC. |
Nat Med. 2005 Mar;11(3):312-9. Epub 2005 Feb 13. |
PMID 15711557 |
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Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy. |
Nicot AS, Toussaint A, Tosch V, Kretz C, Wallgren-Pettersson C, Iwarsson E, Kingston H, Garnier JM, Biancalana V, Oldfors A, Mandel JL, Laporte J. |
Nat Genet. 2007 Sep;39(9):1134-9. Epub 2007 Aug 5. |
PMID 17676042 |
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BAR the door: cancer suppression by amphiphysin-like genes. |
Prendergast GC, Muller AJ, Ramalingam A, Chang MY. |
Biochim Biophys Acta. 2009 Jan;1795(1):25-36. doi: 10.1016/j.bbcan.2008.09.001. Epub 2008 Sep 18. (REVIEW) |
PMID 18930786 |
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Bin1 homolog hob1 supports a Rad6-Set1 pathway of transcriptional repression in fission yeast. |
Ramalingam A, Prendergast GC. |
Cell Cycle. 2007 Jul 1;6(13):1655-62. Epub 2007 May 8. |
PMID 17611416 |
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The BAR domain proteins: molding membranes in fission, fusion, and phagy. |
Ren G, Vajjhala P, Lee JS, Winsor B, Munn AL. |
Microbiol Mol Biol Rev. 2006 Mar;70(1):37-120. (REVIEW) |
PMID 16524918 |
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hob1+, the fission yeast homolog of Bin1, is dispensable for endocytosis or actin organization, but required for the response to starvation or genotoxic stress. |
Routhier EL, Donover PS, Prendergast GC. |
Oncogene. 2003 Feb 6;22(5):637-48. |
PMID 12569356 |
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BIN1 is a novel MYC-interacting protein with features of a tumour suppressor. |
Sakamuro D, Elliott KJ, Wechsler-Reya R, Prendergast GC. |
Nat Genet. 1996 Sep;14(1):69-77. |
PMID 8782822 |
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Bridging integrator 1 (Bin1) deficiency in zebrafish results in centronuclear myopathy. |
Smith LL, Gupta VA, Beggs AH. |
Hum Mol Genet. 2014 Jul 1;23(13):3566-78. doi: 10.1093/hmg/ddu067. Epub 2014 Feb 18. |
PMID 24549043 |
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Bridging integrator 1 (BIN1): form, function, and Alzheimer's disease. |
Tan MS, Yu JT, Tan L. |
Trends Mol Med. 2013 Oct;19(10):594-603. doi: 10.1016/j.molmed.2013.06.004. Epub 2013 Jul 17. (REVIEW) |
PMID 23871436 |
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Mechanisms of Cisplatin-Induced Apoptosis and of Cisplatin Sensitivity: Potential of BIN1 to Act as a Potent Predictor of Cisplatin Sensitivity in Gastric Cancer Treatment. |
Tanida S, Mizoshita T, Ozeki K, Tsukamoto H, Kamiya T, Kataoka H, Sakamuro D, Joh T. |
Int J Surg Oncol. 2012;2012:862879. doi: 10.1155/2012/862879. Epub 2012 Jun 12. |
PMID 22778941 |
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A role for the putative tumor suppressor Bin1 in muscle cell differentiation. |
Wechsler-Reya RJ, Elliott KJ, Prendergast GC. |
Mol Cell Biol. 1998 Jan;18(1):566-75. |
PMID 9418903 |
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Mutations in BIN1 associated with centronuclear myopathy disrupt membrane remodeling by affecting protein density and oligomerization. |
Wu T, Shi Z, Baumgart T. |
PLoS One. 2014 Apr 22;9(4):e93060. doi: 10.1371/journal.pone.0093060. eCollection 2014. |
PMID 24755653 |
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