ITSN2 Gene - Intersectin 2: Function, Mutations, and Disease Associations

ITSN2 (Intersectin 2) encodes a multidomain scaffold protein involved in clathrin-mediated endocytosis, actin cytoskeleton organization, and intracellular signaling. It contains two N-terminal Eps15 homology (EH) domains, a coiled-coil region, and five C-terminal Src homology 3 (SH3) domains. ITSN2 interacts with components of the endocytic machinery and signaling pathways, including Ras, Rac1, and Cdc42. Alternative splicing generates long and short isoforms, with the long isoform including a Dbl homology (DH) and pleckstrin homology (PH) domain that confers guanine nucleotide exchange factor (GEF) activity. ITSN2 is widely expressed, with highest levels in brain and testis.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Endocytosis (KEGG hsa04144)

• Rac1 signaling pathway (Reactome R-HSA-9013408)

• Signaling by Rho GTPases (Reactome R-HSA-194315)

• Clathrin-mediated endocytosis (Reactome R-HSA-8856828)

Intersectin 2 (ITSN2) is a 1,579-amino acid multidomain scaffold protein (UniProt Q9NZM3) that orchestrates clathrin-mediated endocytosis and actin dynamics. The long isoform possesses GEF activity toward Cdc42 and Rac1 via its DH-PH domain, while the short isoform lacks this catalytic region. ITSN2 localizes to clathrin-coated pits and interacts with dynamin, synaptojanin, and Eps15. Its expression is enriched in neuronal tissues, where it regulates synaptic vesicle recycling. Mutations in ITSN2 cause hereditary spastic paraplegia, and dysregulation is linked to cancer and neurodegeneration.