Involved in cell growth regulation. May be involved in the regulation of mitogenic signals and control of cell proliferation. Involved in the internalization of ligand-inducible receptors of the receptor tyrosine kinase (RTK) type, in particular EGFR. Plays a role in the assembly of clathrin-coated pits (CCPs). Acts as a clathrin adapter required for post-Golgi trafficking. Seems to be involved in CCPs maturation including invagination or budding. Involved in endocytosis of integrin beta-1 (ITGB1) and transferrin receptor (TFR); internalization of ITGB1 as DAB2-dependent cargo but not TFR seems to require association with DAB2. Interacts with SGIP1 (PubMed:26822536). Interacts with HGS; the interaction bridges the interaction of STAM or STAM2 with EPS15. Isoform 2 interacts with HGS and AP2A2. Part of a complex at least composed of EPS15, HGS, and either STAM or STAM2. Binds AP2A2. Interacts with AP2B1; clathrin competes with EPS15. Binds STON2. Interacts (via its SH3-binding sites) with CRK. Interacts with SH3BP4/TTP. Interacts with ERBB2. Interacts with FCHO1. Interacts with FCHO2. Interacts (via EH domains) with DAB2. Interacts (via UIM repeats) with CORO7 (when ubiquitinated at 'Lys-472'). Interacts (via UIM domains) with UBQLN1 (via ubiquitin-like domain) and can interact with both the ubiquitinated and the non-ubiquitinated forms of UBQLN1. Interacts with UBQLN2 (By similarity) (PubMed:10757979, PubMed:11062555, PubMed:12551915, PubMed:16159959, PubMed:16314522, PubMed:16325581, PubMed:16903783, PubMed:18199683, PubMed:18200045, PubMed:18362181, PubMed:20448150, PubMed:21762413, PubMed:22484487, PubMed:22648170, PubMed:24768539, PubMed:8662907, PubMed:9721102, PubMed:9723620). Interacts with REPS2; the interaction is direct (PubMed:10393179). Interacts with EPN1; the interaction is direct (PubMed:9723620, PubMed:10393179). (Microbial infection) Interacts with vaccinia virus protein A36. Recruited to the plasma membrane upon EGFR activation and localizes to coated pits. Colocalizes with UBQLN1 in ubiquitin-rich cytoplasmic aggregates that are not endocytic compartments and in cytoplasmic juxtanuclear structures called aggresomes. Colocalizes with HGS on bilayered clathrin coats on endosomes. Ubiquitously expressed. The EH domain interacts with Asn-Pro-Phe (NPF) motifs of target proteins. The UIM (ubiquitin-interacting motif) repeats specifically bind 'Lys-33'-linked ubiquitin. Phosphorylation on Tyr-849 is involved in the internalization of EGFR. Not required for membrane translocation after EGF treatment or for targeting to coated pits, but essential for a subsequent step in EGFR endocytosis (By similarity). Phosphorylated on serine upon DNA damage, probably by ATM or ATR. Ubiquitinated. A chromosomal aberration involving EPS15 is found in acute leukemias. Translocation t(1;11)(p32;q23) with KMT2A/MLL1. The result is a rogue activator protein. Studies in clathrin-mediated endocytosis of ITGB1 and TFR used a siRNA mixture of EPS15 and EPS15L1, 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.