FunctionActivates 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 cells-mediated inflammation by activating ITCH and thus controlling JUNB degradation (By similarity). In cortical neurons, mediates the ubiquitination of SLC11A2/DMT1 by NEDD4L, leading to down-regulation of the divalent metal transporter and protection of the cells from cobalt and iron toxicity. 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.
Tissue specificityWidely expressed. Higher levels are detected in cerebellum, pituitary, thalamus, kidney, liver, testis, salivary glands and placenta. Also expressed in fetal brain, kidney and lung.
DomainThe PY (WW-binding) motifs are required for E3 ubiquitin-protein ligase binding and activation and for ubiquitination.
Post-translational modificationsUbiquitinated by NEDD4 and ITCH; mono-, di- and polyubiquitinated forms are detected. Ubiquitination regulates its degradation. 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.
Cellular localizationEndosome membrane. Golgi apparatus membrane. Secreted. Detected in exosomes and secreted via the exosomal pathway.