BIN1 (bridging integrator 1)

	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).
Description	Bin1 contains N-terminal BAR (Bin1/Amphihysin/Rvs) domain with predicted coiled-coil structure and a C-terminal SH3 domain. 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.
Expression	Bin1 is widely expressed. 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.
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, 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. Membrane binding and tubulation: The Bin1 BAR domain can mediate binding and tubulation of curved membranes. 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. 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. 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. 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. 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. 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. Muscle function: Mutations of the human BIN1 gene are associated with centronuclear myopathy, a disorder marked by severe muscle weakness. Mouse genetic studies indicate that Bin1 is required for cardiac development. In skeletal muscle, Bin1 localizes to T tubules where it appears to support ion flux. In vitro studies of terminal muscle differentiation implicate Bin1 in myoblast cell cycle arrest and fusion during tubule formation. 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. 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. 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. In breast cancer, attenuated expression of Bin1 is associated with increased metastasis and poor clinical outcome. In human tumor cells, ectopic expression of ubiquitous or muscle Bin1 isoforms causes growth arrest or caspase-independent cell death. 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. Mouse genetic studies establish that loss of Bin1 causes lung and liver cancers during aging. In mice where breast or colon tumors are initiated by carcinogen treatment, Bin1 deletion causes progression to more aggressive malignant states. Oncogenically transformed cells lacking Bin1 exhibit reduced susceptibility to apoptosis and increased proliferation, invasion, immune escape, and tumor formation. 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. Null phenotype in mouse: Bin1 knockout mice are perinatal lethal owing to myocardial hypertrophy where myofibrils of ventricular cardiomyocytes are severely disorganized. 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.
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). Bin1 is also closely related to the mammalian amphiphysin-like genes Bin2 and Bin3. Genetic homologs of Bin1 that exist in budding and fission yeast (RVS167 and hob1+) and in fruit flies (amphiphysin) are well-characterized.

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