NDFIP1

The protein encoded by this gene belongs to a small group of evolutionarily conserved proteins with three transmembrane domains. It is a potential target for ubiquitination by the Nedd4 family of proteins. This protein is thought to be part of a family of integral Golgi membrane proteins.

Nedd4 family interacting protein 1

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 (By similarity).

Promotes pancreatic beta cell death through degradation of JUNB and inhibition of the unfolded protein response, leading to reduction of insulin secretion (PubMed:26319551).

Restricts the production of pro-inflammatory cytokines in effector Th17 T-cells by promoting ITCH-mediated ubiquitination and degradation of RORC (By similarity).

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 (By similarity).

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 (By similarity).

Negatively regulates RLR-mediated antiviral response by promoting SMURF1-mediated ubiquitination and subsequent degradation of MAVS (PubMed:23087404).

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 (PubMed:26363003).

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 (PubMed:19706893).

Important for normal development of dendrites and dendritic spines in cortex (By similarity).

Enhances the ubiquitination of BRAT1 mediated by: NEDD4, NEDD4L and ITCH and is required for the nuclear localization of ubiquitinated BRAT1 (PubMed:25631046).

Enhances the ITCH-mediated ubiquitination of MAP3K7 by recruiting E2 ubiquitin-conjugating enzyme UBE2L3 to ITCH (By similarity).

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 (PubMed:20534535).

Inhibits cell proliferation by promoting PTEN nuclear localization and changing its signaling specificity (PubMed:25801959).

Cellular iron ion homeostasis Source: UniProtKB
Metal ion transport Source: GO_Central
Negative regulation of gene expression Source: UniProtKB
Negative regulation of inflammatory response Source: Ensembl
Negative regulation of interleukin-4 production Source: Ensembl
Negative regulation of isotype switching to IgE isotypes Source: Ensembl
Negative regulation of protein transport Source: UniProtKB
Negative regulation of T cell proliferation Source: Ensembl
Negative regulation of transporter activity Source: UniProtKB
Negative regulation of type 2 immune response Source: Ensembl
Positive regulation of I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
Positive regulation of protein catabolic process Source: Ensembl
Positive regulation of protein ubiquitination Source: UniProtKB
Regulation of isotype switching to IgG isotypes Source: Ensembl
Regulation of lymphocyte differentiation Source: Ensembl
Regulation of myeloid leukocyte differentiation Source: Ensembl
Ubiquitin-dependent protein catabolic process Source: GO_Central
Vacuolar transport Source: InterPro

Endosome
Endosome membrane
Secreted
Golgi apparatus
Golgi apparatus membrane
Other locations
synaptosome
dendrite
Note: Detected in exosomes and secreted via the exosomal pathway (PubMed:18819914).

Cytoplasmic: 2-116
Helical: 117-137
Extracellular: 138-143
Helical: 144-164
Cytoplasmic: 165-172
Helical: 173-193
Extracellular: 194-221

Ubiquitinated 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.