Activates HECT domain-containing E3 ubiquitin-protein ligases, including ITCH, NEDD4, NEDD4L, SMURF2, WWP1 and WWP2, and consequently modulates the stability of their targets. As a result, may control many cellular processes. Recruits ITCH, NEDD4 and SMURF2 to endosomal membranes. 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 and multivesicular body where it mediates KCNH2 degradation (By similarity). May modulate EGFR signaling (By similarity). Together with NDFIP1, limits the cytokine signaling and expansion of effector Th2 T-cells by promoting degradation of JAK1, probably by ITCH- and NEDD4L-mediated ubiquitination (PubMed:27088444). Forms heterodimers with NDFIP1 (By similarity). Interacts with HECT domain-containing E3 ubiquitin-protein ligases, including NEDD4 (PubMed:12050153, PubMed:15252135). Interacts with NEDD4L (PubMed:12050153). When phosphorylated at Tyr-142, interacts with SRC and LYN SH2 domain (By similarity). May thus act as a scaffold that recruits SRC to NDFIP1, enhancing NDFIP1 phosphorylation (By similarity). Interacts with SLC11A2/DMT1 (By similarity). May interact with phosphorylated EGFR (By similarity). Interacts with KCNH2 (By similarity). Ubiquitously expressed, with highest levels in brain, liver, kidney and testis. The PPxY motifs are required for E3 ubiquitin-protein ligase activation and for ubiquitination. Ubiquitinated by NEDD4 and NEDD4L; which does not affect turnover (Probable). Also ubiquitinated by ITCH (By similarity). Undergoes transient tyrosine-phosphorylation following EGF stimulation, most probably catalyzed by SRC. Phosphorylation on Tyr-126, Tyr-146 and Tyr-152 are dependent on the phosphorylation on Tyr-142. Also phosphorylated by LYN and FYN (By similarity). Mutant mice show no signs of inflammation and have normal T-cell populations in thymus, lymph nodes and spleen.