Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10162)
Regulator Name E3 ubiquitin-protein ligase NEDD4 (NEDD4)
Synonyms
Cell proliferation-inducing gene 53 protein; HECT-type E3 ubiquitin transferase NEDD4; Neural precursor cell expressed developmentally down-regulated protein 4
    Click to Show/Hide
Gene Name NEDD4
Gene ID 4734
Regulator Type Protein coding
Uniprot ID P46934
Sequence
MAQSLRLHFAARRSNTYPLSETSGDDLDSHVHMCFKRPTRISTSNVVQMKLTPRQTALAP
LIKENVQSQERSSVPSSENVNKKSSCLQISLQPTRYSGYLQSSNVLADSDDASFTCILKD
GIYSSAVVDNELNAVNDGHLVSSPAICSGSLSNFSTSDNGSYSSNGSDFGSCASITSGGS
YTNSVISDSSSYTFPPSDDTFLGGNLPSDSTSNRSVPNRNTTPCEIFSRSTSTDPFVQDD
LEHGLEIMKLPVSRNTKIPLKRYSSLVIFPRSPSTTRPTSPTSLCTLLSKGSYQTSHQFI
ISPSEIAHNEDGTSAKGFLSTAVNGLRLSKTICTPGEVRDIRPLHRKGSLQKKIVLSNNT
PRQTVCEKSSEGYSCVSVHFTQRKAATLDCETTNGDCKPEMSEIKLNSDSEYIKLMHRTS
ACLPSSQNVDCQININGELERPHSQMNKNHGILRRSISLGGAYPNISCLSSLKHNCSKGG
PSQLLIKFASGNEGKVDNLSRDSNRDCTNELSNSCKTRDDFLGQVDVPLYPLPTENPRLE
RPYTFKDFVLHPRSHKSRVKGYLRLKMTYLPKTSGSEDDNAEQAEELEPGWVVLDQPDAA
CHLQQQQEPSPLPPGWEERQDILGRTYYVNHESRRTQWKRPTPQDNLTDAENGNIQLQAQ
RAFTTRRQISEETESVDNRESSENWEIIREDEATMYSNQAFPSPPPSSNLDVPTHLAEEL
NARLTIFGNSAVSQPASSSNHSSRRGSLQAYTFEEQPTLPVLLPTSSGLPPGWEEKQDER
GRSYYVDHNSRTTTWTKPTVQATVETSQLTSSQSSAGPQSQASTSDSGQQVTQPSEIEQG
FLPKGWEVRHAPNGRPFFIDHNTKTTTWEDPRLKIPAHLRGKTSLDTSNDLGPLPPGWEE
RTHTDGRIFYINHNIKRTQWEDPRLENVAITGPAVPYSRDYKRKYEFFRRKLKKQNDIPN
KFEMKLRRATVLEDSYRRIMGVKRADFLKARLWIEFDGEKGLDYGGVAREWFFLISKEMF
NPYYGLFEYSATDNYTLQINPNSGLCNEDHLSYFKFIGRVAGMAVYHGKLLDGFFIRPFY
KMMLHKPITLHDMESVDSEYYNSLRWILENDPTELDLRFIIDEELFGQTHQHELKNGGSE
IVVTNKNKKEYIYLVIQWRFVNRIQKQMAAFKEGFFELIPQDLIKIFDENELELLMCGLG
DVDVNDWREHTKYKNGYSANHQVIQWFWKAVLMMDSEKRIRLLQFVTGTSRVPMNGFAEL
YGSNGPQSFTVEQWGTPEKLPRAHTCFNRLDLPPYESFEELWDKLQMAIENTQGFDGVD

    Click to Show/Hide
Function
E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Specifically ubiquitinates 'Lys-63' in target proteins. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. Promotes ubiquitination of RAPGEF2. According to the direct link between NEDD4 and PTEN regulation through polyubiquitination described in is questionable. Involved in ubiquitination of ERBB4 intracellular domain E4ICD. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1. Ubiquitinates DAZAP2, leading to its proteasomal degradation. Ubiquitinates POLR2A.

    Click to Show/Hide
HGNC ID
HGNC:7727
KEGG ID hsa:4734
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
NEDD4 can regulate the following target(s), and cause disease/drug response(s). You can browse detail information of target(s) or disease/drug response(s).
Browse Target
Browse Disease
Browse Drug
Voltage-dependent anion-selective channel protein 2 (VDAC2) [Suppressor]
 Target Info 
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Driver
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Responsed Drug Robustaflavone Investigative
 Drug Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 MCF-7 cells Breast carcinoma Homo sapiens CVCL_0031
Response regulation Robustaflavone A strikingly induced MCF-7 nonapoptotic cell death through ferroptosis by enhancing the expression of VDAC2 channels and reducing the expression of Nedd4 E3 ubiquitin ligase, leading to lipid peroxidation and ROS production. The results suggested that RF-A has potential as a novel breast cancer treatment through its regulation of the mitochondrial VDAC2 and Nedd4 pathways.
Experiment 2 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Driver/Suppressor
Responsed Disease Melanoma ICD-11: 2C30
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 A-375 cells Amelanotic melanoma Homo sapiens CVCL_0132
G-361 cells Melanoma Homo sapiens CVCL_1220
MeWo cells Melanoma Homo sapiens CVCL_0445
SK-MEL-2 cells (MEK inhibitor-resistant) cells Melanoma Homo sapiens CVCL_0069
SK-MEL-3 cells Cutaneous melanoma Homo sapiens CVCL_0550
SK-MEL-24 cells Melanoma Homo sapiens CVCL_0599
WM2032 cells Melanoma Homo sapiens CVCL_0B68
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
NU/NU Nude mice were purchased from Charles River (Beijing). To generate murine subcutaneous tumors, melanoma cells (5 x 106 cells per mouse) were injected subcutaneously into the left posterior flanks of 7-week-old immunodeficient female nude mice.

    Click to Show/Hide
Response regulation Knockdown of Nedd4 leads to elevated protein level of VDAC2/3, which increased the sensitivity of melanoma cells to erastin both in vitro and in vivo.
Voltage-dependent anion-selective channel protein 3 (VDAC3) [Suppressor]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Driver/Suppressor
Responsed Disease Melanoma ICD-11: 2C30
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 A-375 cells Amelanotic melanoma Homo sapiens CVCL_0132
G-361 cells Melanoma Homo sapiens CVCL_1220
MeWo cells Melanoma Homo sapiens CVCL_0445
SK-MEL-2 cells (MEK inhibitor-resistant) cells Melanoma Homo sapiens CVCL_0069
SK-MEL-3 cells Cutaneous melanoma Homo sapiens CVCL_0550
SK-MEL-24 cells Melanoma Homo sapiens CVCL_0599
WM2032 cells Melanoma Homo sapiens CVCL_0B68
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
NU/NU Nude mice were purchased from Charles River (Beijing). To generate murine subcutaneous tumors, melanoma cells (5 x 106 cells per mouse) were injected subcutaneously into the left posterior flanks of 7-week-old immunodeficient female nude mice.

    Click to Show/Hide
Response regulation Knockdown of Nedd4 leads to elevated protein level of VDAC2/3, which increased the sensitivity of melanoma cells to erastin both in vitro and in vivo.
Breast cancer [ICD-11: 2C60]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator E3 ubiquitin-protein ligase NEDD4 (NEDD4) Protein coding
 Regulator Info 
Responsed Drug Robustaflavone Investigative
 Drug Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 MCF-7 cells Breast carcinoma Homo sapiens CVCL_0031
Response regulation Robustaflavone A strikingly induced MCF-7 nonapoptotic cell death through ferroptosis by enhancing the expression of VDAC2 channels and reducing the expression of Nedd4 E3 ubiquitin ligase, leading to lipid peroxidation and ROS production. The results suggested that RF-A has potential as a novel breast cancer treatment through its regulation of the mitochondrial VDAC2 and Nedd4 pathways.
Melanoma [ICD-11: 2C30]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator E3 ubiquitin-protein ligase NEDD4 (NEDD4) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 A-375 cells Amelanotic melanoma Homo sapiens CVCL_0132
G-361 cells Melanoma Homo sapiens CVCL_1220
MeWo cells Melanoma Homo sapiens CVCL_0445
SK-MEL-2 cells (MEK inhibitor-resistant) cells Melanoma Homo sapiens CVCL_0069
SK-MEL-3 cells Cutaneous melanoma Homo sapiens CVCL_0550
SK-MEL-24 cells Melanoma Homo sapiens CVCL_0599
WM2032 cells Melanoma Homo sapiens CVCL_0B68
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
NU/NU Nude mice were purchased from Charles River (Beijing). To generate murine subcutaneous tumors, melanoma cells (5 x 106 cells per mouse) were injected subcutaneously into the left posterior flanks of 7-week-old immunodeficient female nude mice.

    Click to Show/Hide
Response regulation Knockdown of Nedd4 leads to elevated protein level of VDAC2/3, which increased the sensitivity of melanoma cells to erastin both in vitro and in vivo.
Robustaflavone [Investigative]
 Drug Info 
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Inducer
Response Target Voltage-dependent anion-selective channel protein 2 (VDAC2) Suppressor
 Target Info 
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
 MCF-7 cells Breast carcinoma Homo sapiens CVCL_0031
Response regulation Robustaflavone A strikingly induced MCF-7 nonapoptotic cell death through ferroptosis by enhancing the expression of VDAC2 channels and reducing the expression of Nedd4 E3 ubiquitin ligase, leading to lipid peroxidation and ROS production. The results suggested that RF-A has potential as a novel breast cancer treatment through its regulation of the mitochondrial VDAC2 and Nedd4 pathways.
References
Ref 1 Identification of a new natural biflavonoids against breast cancer cells induced ferroptosis via the mitochondrial pathway. Bioorg Chem. 2021 Apr;109:104744. doi: 10.1016/j.bioorg.2021.104744. Epub 2021 Feb 17.
Ref 2 Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma. Nat Commun. 2020 Jan 23;11(1):433. doi: 10.1038/s41467-020-14324-x.