Activates HECT domain-containing E3 ubiquitin-protein ligases, including NEDD4 and ITCH, and consequently modulates the stability of their targets. As a result, controls many cellular processes. Prevents chronic T-helper cell-mediated inflammation by activating ITCH and thus controlling JUNB degradation. Promotes pancreatic beta cell death through degradation of JUNB and inhibition of the unfolded protein response, leading to reduction of insulin secretion. Restricts the production of pro-inflammatory cytokines in effector Th17 T-cells by promoting ITCH-mediated ubiquitination degradation of RORC. Together with NDFIP2, limits the cytokine signaling and expansion of effector Th2 T-cells by promoting degradation of JAK1, probably by ITCH- and NEDD4L-mediated ubiquitination. Regulates peripheral T-cell tolerance to self and foreign antigens, forcing the exit of naive CD4+ T-cells from the cell cycle before they become effector T-cells. Negatively regulates RLR-mediated antiviral response by promoting SMURF1-mediated ubiquitination and subsequent degradation of MAVS. Negatively regulates KCNH2 potassium channel activity by decreasing its cell-surface expression and interfering with channel maturation through recruitment of NEDD4L to the Golgi apparatus where it mediates KCNH2 degradation. In cortical neurons, mediates the ubiquitination of the divalent metal transporter SLC11A2/DMT1 by NEDD4L, leading to its down-regulation and protection of the cells from cobalt and iron toxicity. Important for normal development of dendrites and dendritic spines in cortex. Enhances the ubiquitination of BRAT1 mediated by: NEDD4, NEDD4L and ITCH and is required for the nuclear localization of ubiquitinated BRAT1. Enhances the ITCH-mediated ubiquitination of MAP3K7 by recruiting E2 ubiquitin-conjugating enzyme UBE2L3 to ITCH. Modulates EGFR signaling through multiple pathways. In particular, may regulate the ratio of AKT1-to-MAPK8 signaling in response to EGF, acting on AKT1 probably through PTEN destabilization and on MAPK8 through ITCH-dependent MAP2K4 inactivation. As a result, may control cell growth rate. Inhibits cell proliferation by promoting PTEN nuclear localization and changing its signaling specificity. Forms heterodimers with NDFIP2. Interacts with several E3 ubiquitin-protein ligases, including ITCH, NEDD4, NEDD4L and WWP2. The interaction with NEDD4, NEDD4L and ITCH leads to relocalization of these proteins to exosomes and eventually to exosomal secretion. Interacts with SR1402. Interacts with SLC11A2/DMT1. Interacts with PTEN. May interact with phosphorylated EGFR. Interacts with BRAT1. Interacts with KCNH2. Interacts with MAVS. Part of a complex containing ITCH, NDFIP1 and MAP3K7. Interacts (via N-terminus) with UBE2L3; the interaction mediates recruitment of UBE2L3 to ITCH. Detected in exosomes and secreted via the exosomal pathway. The PPxY motifs are required for E3 ubiquitin-protein ligase binding and activation and for ubiquitination. Ubiquitinated by NEDD4; mono-, di- and polyubiquitinated forms are detected. Ubiquitination regulates its degradation (By similarity). Undergoes transient tyrosine phosphorylation following EGF stimulation, most probably by catalyzed by SRC. Phosphorylation SRC is enhanced in the presence of NDFIP2 which may act as a scaffold to recruit SRC to NDFIP1 (By similarity).