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FLASH GENE
Symbol ITSN1 contributors: mct - updated : 13-11-2018
HGNC name intersectin 1 (SH3 domain protein)
HGNC id 6183
RNA
TRANSCRIPTS type messenger
text identification of fifteen novel transcriptional isoforms of the human ITSN1 gene with full-length coding sequences that are the result of different combinations of the alternatively spliced exons 5, 6/6', 20, 23, 25, 26, 26a and 35 (PMID: 19777371)
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
40 splicing 6439 195.3 1721 brain specific (neuron-specific isoform)(PMID: 19258322) 2010 19777371
  • involved in brain-specific synaptic vesicle recycling
  • long isoform ITSN1L
  • contains three additional domains, a Dbl homology (DH) domain, a Pleckstrin homology (PH) domain and a C2 domain
  • specific GEF for CDC42
  • may regulate multiple forms of endocytosis in mammalian neurons, including synaptic vesicle endocytosis
  • important regulator of constitutive endocytosis and neuronal development
  • may be more important for regulating neuronal differentiation versus oncogenic transformation (PMID: 22266851)
    • 30 splicing 5451 137.5 1220 ubiquitous; expressed in multiple tissues and cells, including glia, but excluded from neurons (PMID: 19258322) 2010 19777371
  • short isoform, ITSN1s
  • differing in the 3' UTR and coding region compared to variant 1
  • two Eps15 homology (EH) domains and five Src homology 3 (SH3) domains
  • multimodule scaffolding protein functioning in constitutive and regulated forms of endocytosis in non-neuronal cells and in synaptic vesicle
  • critical roles of ITSN1-S in malignant glioma proliferation (PMID: 25832561)
  • monoubiquitination is required for ITSN1-s stability (PMID: 29851086)
    • - - - - - - 2011 21712076
  • two EH domains, a coiled-coil region, an SH3A domain and a specific C-terminal domain (CTD) but lacks four SH3 domains in comparison with ITSN1s
  • binds via its CTD to the SH3 domain of the endocytic protein amphiphysin 1 and the SH3A domain of ITSN1
  • in contrast to ITSN1s did not interact with CBL
  • possesses a significantly altered domain structure and performs specific protein-protein interactions
  • undergoes a combination of mono- and oligoubiquitination (PMID: 29851086)
    • 28 - 5330 - 1149 - 2017 28161632
    29 - 5528 - 1215 - 2017 28161632
    39 - 6881 - 1716 - 2017 28161632
    27 - 5315 - 1144 - 2017 28161632
    29 - 5417 - 1178 - 2017 28161632
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   moderately
     vessel   moderately
    Digestiveliver    
    Hearing/Equilibriumearinnercochlea moderately
    Nervousbraindiencephalonamygdala  
     nervecranial nerve  predominantly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectiveadipose  highly
    Connectivebone   
    Muscularstriatumskeletal  
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal
    Text moderately in umbilical cord, proliferating and differentiating neurons
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • two EH (Eps 15 homology) domains
  • two EF-hand domains
  • five SH3 (Src homolog 3) domains
  • a DH (DBL-homology) domain
  • a PH (pleckstrin homology)
  • a C2 domains
  • in the long form a GET (guanine nucleotide exchange factor)
    • secondary structure
  • a central alpha helix forming a coiled coil region
    • HOMOLOGY
    interspecies homolog to rattus Itsn1 (94.8 pc)
    homolog to murine Itsn1 (95 pc)
    Homologene
    FAMILY
    CATEGORY adaptor
    SUBCELLULAR LOCALIZATION     plasma membrane,junction
        intracellular
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,cytosolic,vesicle
    text
  • colocalization of ITSN1 with the newly identified protein partners in clathrin-coated pits
  • co-localization of ITSN1 and WIPF1 at sites of invadopodia formation and in clathrin-coated pits
    • basic FUNCTION
  • involved in membrane associated molecular trafficking and clathrin mediated endocytosis
  • may provide indirect link between the endocytic membrane traffic and the actin assembly machinery
  • may regulate the formation of clathrin-coated vesicles
  • involved in receptor endocytosis regulation
  • ITSN1 and ITSN2 are conserved proteins involved in clathrin-mediated endocytosis
  • conserved adaptor protein implicated in endocytosis, regulation of actin cytoskeleton rearrangements and mitogenic signaling
  • alternative splicing leads to the formation of two pools of ITSN1 with potentially different properties in neurons, affecting ITSN1 function as adaptor protein
  • molecular link between INPPL1 and ITSN1 which are involved in receptor endocytosis regulation
  • adaptor protein involved in clathrin-mediated endocytosis, cellular signaling and cytoskeleton rearrangement
  • role of ITSN1 as a scaffolding molecule bringing together components of endocytic complexes
  • functions as a scaffolding protein regulating many aspects of membrane traffic
  • adaptor protein engaged in clathrin-mediated endocytosis, cell signaling and actin cytoskeleton rearrangements
  • ITSN1 is an important component in the anchorage-independent growth of neuroblastoma (NB) cells
  • is important for the tumorigenic potential of NB cells
  • ITSN1 and ITSN2, are crucial for the initiation stage of clathrin-mediated endocytosis
  • ITSN1, ITSN2 are scaffold proteins involved in the molecular mechanisms of invadopodia formation
  • is a multidomain adapter protein implicated in endocytosis, exocytosis, and multiple signaling pathways
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS endocytosis transport
    text
  • synaptic vesicle endocytosis
    • PATHWAY
    metabolism
    signaling signal transduction
  • regulation of Rho protein signal transduction
    • a component
  • constituent of endocyte machinery
  • ITSN1, ITSN2 form homomeric and heteromeric complexes with each other revealing an added level of complexity in the function of these evolutionarily conserved scaffolds
  • WIPF1/ITSN1 complex is involved in the cellular vesicle trafficking and actin-dependent membrane processes
    • INTERACTION
    DNA
    RNA
    small molecule metal binding,
  • Ca2+
    • protein
  • synaptogamin
  • interacting with dynamin
  • interacting with SNAP25
  • interacting with SNAP23
  • binding clathrin-associated proteins and other components of the endocytic machinery, such as SPIN90, EPS15, EPN1, EPN2 and STON2
  • binding to INPPL1 via Src homology 3D, A, C, and E domains
  • intersectin and EPS15 proteins function in the same genetic pathway, and appear to function synergistically with the clathrin-coat-associated sorting protein, Disabled, for viability
  • SGIP1 and the signaling adaptor REPS1 interact with ITSN1
  • intersectin-SH3D/ARHGAP31 interaction (interacts directly with a small region of ARHGAP31 highly enriched in basic residues and comprising a novel conserved xKx(K/R)K motif)
  • binding partner of the SH2 domain containing inositol 5-phosphatase 2 (INPPL1)
  • interaction between CDC42 and intersectin (ITSN1), a specific CDC42 guanine nucleotide exchange factor
  • ITSN1 is an important general regulator of CDC42-, NCK1- and WASL-dependent actin polymerisation
  • WIPF1 interacts with endocytic adaptor proteins of the intersectin (ITSN) family, ITSN1 and ITSN2
  • ITSN1 is a component of RELN signaling that acts predominantly by facilitating the VLDLR-DAB1 axis to direct neuronal migration in the cortex and hippocampus and to augment synaptic plasticity
  • ITSN1 and ITSN2 are podocytic guanine nucleotide exchange factors for CDC42
  • ITCH contributes to the differential ubiquitination of isoforms of the endocytic scaffold protein intersectin1 (ITSN1)
  • WIPF1 interaction with ITSN1 highly implicated in endo-/exocytosis, apoptosis, mitogenic signaling and cytoskeleton rearrangements
    • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) DEL21QD
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    overexpressed in brain from Down syndrome patients
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancer  
    ZCL278 is a small molecule that specifically targets CDC42–ITSN1 interaction and inhibits CDC42-mediated cellular processes, thus providing a tool for research of CDC42 subclass of Rho GTPases in pathogenesis, such as cancer and neurological disorders
    ANIMAL & CELL MODELS