Adapter protein that provides a link between the endocytic membrane traffic and the actin assembly machinery (PubMed:11584276, PubMed:29887380). Acts as guanine nucleotide exchange factor (GEF) for CDC42, and thereby stimulates actin nucleation mediated by WASL and the ARP2/3 complex (PubMed:11584276). Plays a role in the assembly and maturation of clathrin-coated vesicles (By similarity). Recruits FCHSD2 to clathrin-coated pits (PubMed:29887380). Involved in endocytosis of activated EGFR, and probably also other growth factor receptors (By similarity). Involved in endocytosis of integrin beta-1 (ITGB1) and transferrin receptor (TFR); internalization of ITGB1 as DAB2-dependent cargo but not TFR may involve association with DAB2 (PubMed:22648170). Promotes ubiquitination and subsequent degradation of EGFR, and thereby contributes to the down-regulation of EGFR-dependent signaling pathways. In chromaffin cells, required for normal exocytosis of catecholamines. Required for rapid replenishment of release-ready synaptic vesicles at presynaptic active zones (By similarity). Inhibits ARHGAP31 activity toward RAC1 (PubMed:11744688). Plays a role in synaptic vesicle endocytosis in brain neurons. Interacts (via DH domain) with CDC42 (PubMed:11584276, PubMed:12006984). Interacts (via SH3 domain 1) with WASL (PubMed:11584276). Interacts with dynamin, SNAP25 and SNAP23 (By similarity). Interacts with clathrin-associated proteins and other components of the endocytic machinery, such as SPIN90, EPS15, EPN1, EPN2, STON2, FCHO1, FCHO2 and DAB2 (PubMed:20448150, PubMed:22484487, PubMed:22648170). Interacts (via SH3 domains) with REPS1 and SGIP1 (PubMed:20946875). Interacts with ARHGAP31 (PubMed:11744688). Interacts with ADAM15 (PubMed:19718658). Interacts with PRRT2 (By similarity). Interacts (via SH3 domain 4) with FCHSD2 (via SH3 domain 2) (PubMed:29887380). Interacts (via SH3 domain 1) with DENND2B (PubMed:29030480). Interacts (via SH3 domains) with CBL (By similarity). Isoform 2: Interacts with CBL and DNM1 (PubMed:21712076). Isoform 2: Interacts with LMNA (PubMed:29599122). Isoform 2: Interacts with importin subunit KPNA1; this is likely to mediate its import into the nucleus (PubMed:29599122). (Microbial infection) Interacts with vaccinia virus protein A36 (PubMed:27670116). Colocalizes with SGIP1 at the plasma membrane in structures corresponding most probably to clathrin-coated pits (PubMed:20946875). Colocalizes with RAB13 on cytoplasmic vesicles that are most likely recycling endosomes (PubMed:29030480). Shuttles between the cytoplasm and nucleus in an XPO1/CRM1-dependent manner. Additional isoforms seem to exist. Alternative splicing affects domains involved in protein recognition and thus may play a role in selecting specific interactions. Isoform 1 is expressed almost exclusively in the brain. Isoform 2 is detected in brain, spleen, lung, liver, heart, skeletal muscle and kidney. Isoform 5 is primarily expressed in brain, spleen, lung and kidney (at protein level) (PubMed:21712076). Isoform 1 and isoform 2 are detected in brain (PubMed:10482960). Isoform 2 is ubiquitous in adult and fetal tissues with high expression in skeletal muscle, heart, spleen, ovary, testis and all fetal tissues tested and low expression in thymus, blood, lung, liver and pancreas. Isoform 1 is expressed almost exclusively in the brain, in all brain regions. Not expressed in the spinal cord (PubMed:9799604, PubMed:21712076, PubMed:11690630). SH3-3, SH3-4 and SH3-5, but not SH3-1 and SH3-2 domains, bind to dynamin (By similarity). SH3-1 and SH3-4 bind to ARHGAP31. The KLERQ domain binds to SNAP-25 and SNAP-23. In an autoinhibited form the SH3 domain 5 may bind intramolecularly to the DH domain, thus blocking the CDC42-binding site. Contains a premature stop codon, potentially subjected to NMD. Contains a premature stop codon, potentially subjected to NMD. Studies in clathrin-mediated endocytosis of ITGB1 and TFR used a siRNA mixture of ISTN1 and ISTN2, and a Dab2 mutant with impaired binding to EH domain-containing proteins EPS15 and ITSN1 suggesting a partially overlapping role of the EH domain-containing proteins.