The Ubiquitin Ligase Table provides a list of E3 ubiquitin ligases, along with their substrates (when known), and corresponding references. This table was generated using PhosphoSitePlus®, Cell Signaling Technology’s protein modification resource.

Ubiquitin Ligase Table

Ligase Substrate Function References
Ligase Substrate Function References
AMFR KAI1 AMFR is also known as gp78. AMFR is an integral ER membrane protein and functions in ER-associated degradation (ERAD). AMFR has been found to promote tumor metastasis through ubiquitination of the metastasis supressor, KAI1. (1)
APC/Cdc20 Cyclin B The anaphase promoting complex/cyclosome (APC/C) is a multiprotein complex with E3 ligase activity that regulates cell cycle progression through degradation of cyclins and other mitotic proteins. APC is found in a complex with CDC20, CDC27, SPATC1, and TUBG1. (2)
APC/Cdh1 Cdc20, Cyclin B, Cyclin A, Aurora A, Securin, Skp2, Claspin The anaphase promoting complex/cyclosome (APC/C) is a multiprotein complex with E3 ligase activity that regulates cell cycle progression through degradation of cyclins and other mitotic proteins. The APC/C-Cdh1 dimeric complex is activated during anaphase and telophase, and remains active until onset of the next S phase. (3, 4, 5, 6, 7)
C6orf157 Cyclin B C6orf157 is also known as H10BH. C6orf157 is an E3 ubiquitin ligase that has been shown to ubiquitinate cyclin B. (8)
Cbl   Cbl-b and c-Cbl are members of the Cbl family of adaptor proteins that are highly expressed in hematopoietic cells. Cbl proteins possess E3 ubiquitin ligase activity that downregulates numerous signaling proteins and RTKs in several pathways such as EGFR, T cell and B cell receptors, and integrin receptors. Cbl proteins play an important role in T cell receptor signaling pathways. (9, 10)
CBLL1 CDH1 CBLL1 is also known as Hakai. CBLL1 is an E3 ubiquitin ligase that ubiquitinates the phosphorylated form of E-Cadherin, causing its degradation and loss of cell-cell adhesions. (11)
CHFR PLK1, Aurora A CHFR is an E3 ubiquitin ligase that functions as a mitotic stress checkpoint protein that delays entry into mitosis in response to stress. CHFR has been shown to ubiquitinate and degrade the kinases PLK1 and Aurora A. (12, 13)
CHIP HSP70/90, iNOS, Runx1, LRRK2 CHIP is an E3 ubiquitin ligase that acts as a co-chaperone protein and interacts with several heat shock proteins, including HSP70 and HSP90, as well as the non-heat shock proteins iNOS, Runx1 and LRRK2. (14, 15, 16, 17)
DTL (Cdt2) p21 DTL is an E3 ubiquitin ligase that complexes with Cullin4 and DDB1, and promotes p21 degradation after UV damage. (18)
E6-AP p53, Dlg E6-AP is also known as UBE3A. E6-AP is a HECT domain E3 ubiquitin ligase that interacts with Hepatitis C virus (HCV) core protein and targets it for degradation. The HCV core protein is central to packaging viral DNA and other cellular processes. E6-AP also interacts with the E6 protein of the human papillomavirus types 16 and 18, and targets the p53 tumor-suppressor protein for degradation. (19)
HACE1   HACE1 is an E3 ubiquitin ligase and tumor suppressor. Aberrant methylation of HACE1 is frequently found in Wilms’ tumors and colorectal cancer. (20)
HECTD1   HECTD1 is an ubiquitin E3 ligase required for neural tube closure and normal development of the mesenchyme. (21)
HECTD2   HECTD2 is a probable E3 ubiquitin ligase and may act as a succeptibility gene for neurodegeneration and prion disease. (22)
HECTD3   HECTD3 is a probable E3 ubiquitin ligase and may play a role in cytoskeletal regulation, actin remodeling, and vesicle trafficking. (23)
HECW1 DVL1, mutant SOD1, p53 HECW1 is also known as NEDL1. HECW1 interacts with p53 and the Wnt signaling protein DVL1, and may play a role in p53-mediated cell death in neurons. (24, 25)
HECW2 p73 HECW2 is also known as NEDL2. HECW2 ubiquitinates p73, which is a p53 family member. Ubiquitination of p73 increases protein stability. (26)
HERC2 RNF8 HERC2 belongs to a family of E3 ubiquitin ligases involved in membrane trafficking events. HERC2 plays a role in the DNA damage response through interaction with RNF8. (27)
HERC3   HERC3 belongs to a family of E3 ubiquitin ligases involved in membrane trafficking events. HERC3 interacts with hPLIC-1 and hPLIC-2 and localizes to the late endosomes and lysosomes. (28)
HERC4   HERC4 belongs to a family of E3 ubiquitin ligases involved in membrane trafficking events. HERC4 is highly expressed in testis and may play a role in spermatogenesis. (29)
HERC5   HERC5 belongs to a family of E3 ubiquitin ligases involved in membrane trafficking events. HERC5 is induced by interferon and other pro-inflammatory cytokines and plays a role in interferon-induced ISG15 conjugation during the innate immune response. (30, 31)
HUWE1 N-Myc, C-Myc, p53, Mcl-1, TopBP1 HUWE1 is also known as Mule. HUWE1 is a HECT domain E3 ubiquitin ligase that regulates degradation of Mcl-1 and therefore regulates DNA damage-induced apoptosis. HUWE1 also controls neuronal differentiation by destabilizing N-Myc, and regulates p53-dependent and independent tumor suppression via ARF. (32)
HYD CHK2 HYD is also known as EDD or UBR5. HYD is a regulator of the DNA damage response and is overexpressed in many forms of cancer. (33)
ITCH MKK4, RIP2, Foxp3 ITCH plays a role in T cell receptor activation and signaling through ubiquitination of multiple proteins including MKK4, RIP2 and Foxp3. Loss of ITCH function leads to an abberrant immune response and T helper cell differentiation. (34, 35, 36)
LNX1 NUMB LNX1 is an E3 ubiquitin ligase that plays a role in cell fate determination during embryogenesis through regulation of NUMB, the negative regulator of Notch signaling. (37)
mahogunin   Mahogunin is an E3 ubiquitin ligase involved in melanocortin signaling. Loss of mahogunin function leads to neurodegeneration and loss of pigmentation, and may be the mechanism of action in prion disease. (38, 39)
MARCH-I HLA-DRβ MARCH1 is an E3 ubiquitin ligase found on antigen presenting cells (APCs). MARCH1 ubiquitinates MHC class II proteins and downregulates their cell surface expression. (40)
MARCH-II   MARCH-II is a member of the MARCH family of E3 ubiquitin ligases. It associates with syntaxin6 in the endosomes and helps to regulate vesicle trafficking. (41)
MARCH-III   MARCH-III is a member of the MARCH family of E3 ubiquitin ligases. MARCH-III associates with syntaxin6 in the endosomes and helps to regulate vesicle trafficking. (42)
MARCH-IV MHC class I MARCH-IV is a member of the MARCH family of E3 ubiquitin ligases. MARCH-IV ubiquitinates MHC class I proteins and downregulates their cell surface expression. (43)
MARCH-VI   MARCH-VI is also known as TEB4 and is a member of the MARCH family of E3 ubiquitin ligases. It localizes to the endoplasmic reticulum and participates in ER-associated protein degradation. (44)
MARCH-VII gp190 MARCH-VII is also known as axotrophin. MARCH-VII was originally identified as a neural stem cell gene, but has since been shown to play a role in LIF signaling in T lymphocytes through degradation of the LIF-receptor subunit, gp190. (45)
MARCH-VIII B7-2, MHC class II MARCH-VIII is also known as c-MIR. MARCH-VIII causes the ubiquitination/degradation of B7-2, which is a co-stimulatory molecule for antigen presentation. MARCH-VIII has also been shown to ubiquitinate MHC class II proteins. (46)
MARCH-X   MARCH-X is also known as RNF190. MARCH-X is a member of the MARCH family of E3 ubiquitin ligases. The putative role of MARCH-X is not currently known.  
MDM2 p53 MDM2, an E3 ubiquitin ligase for p53, plays a central role in regulation of the stability of p53. Akt-mediated phosphorylation of MDM2 at Ser166 and Ser186 increases its interaction with p300, allowing MDM2-mediated ubiquitination and degradation of p53. (47)
MEKK1 c-Jun, Erk MEKK1 is a well known protein kinase of the STE11 family. MEKK1 phosphorylates and activates MKK4/7, which in turn activates JNK1/2/3. MEKK1 contains a RING finger domain and exhibits E3 ubiquitin ligase activity toward c-Jun and Erk. (48, 49)
MIB1 Delta, Jagged Mindbomb homolog 1 (MIB1) is an E3 ligase that facilitates the ubiquitination and subsequent endocytosis of the Notch ligands, Delta and Jagged. (50)
MIB2 Delta, Jagged Mind Bomb 2 (MIB2) is an E3 ligase that positively regulates Notch Signaling. MIB2 has been shown to play a role in myotube differentiation and muscle stability. MIB2 ubiquitinates NMDAR subunits to help regulate synaptic plasticity in neurons. (51, 52, 53)
MycBP2 Fbxo45, TSC2 MycBP2 is an E3 ubiquitin ligase also known as PAM. MycBP2 associates with Fbxo45 to play a role in neuronal development. MycBP2 also regulates the mTOR pathway through ubiquitination of TSC2. (54, 55)
NEDD4   NEDD4 is an E3 ubiquitin ligase highly expressed in the early mouse embryonic central nervous system. NEDD4 downregulates both neuronal voltage-gated Na+ channels (NaVs) and epithelial Na+ channels (ENaCs) in response to increased intracellular Na+ concentrations. (56, 57)
NEDD4L Smad2 NEDD4L is an E3 ubiquitin ligase highly expressed in the early mouse embryonic central nervous system. NEDD4L has been shown to negatively regulate TGF-β signaling by targeting Smad2 for degradation. (58)
Parkin   Parkin is an E3 ubiquitin ligase that has been shown to be a key regulator of the autophagy pathway. Mutations in Parkin can lead to Parkinson’s Disease. (59)
PELI1 TRIP, IRAK PELI1 is an E3 ubiquitin ligase that plays a role in Toll-like Receptor (TLR3 and TLR4) signaling to NF-κB via the TRIP adaptor protein. PELI1 has also been shown to ubiquitinate IRAK. (60, 61)
Pirh2 TP53 Pirh2 is also known as RCHY1. Pirh2 is a RING domain E3 ubiquitin ligase. Pirh2 binds p53 and promotes proteosomal degradation of p53 independent of MDM2. Pirh2 gene expression is controlled by p53, making this interaction part of an autoinhibitory feedback loop. (62, 63)
PJA1 ELF PJA1 is also known as PRAJA. PJA1 plays a role in downregulating TGF-β signaling in gastric cancer via ubiquitination of the SMAD4 adaptor protein ELF. (64)
PJA2   PJA2 is an E3 ubiquitin ligase found in neuronal synapses. The exact role and substrates of PJA2 are unclear. (65)
RFFL p53 RFFL is also known as CARP2 and is an E3 ubiquitin ligase that inhibits endosome recycling. RFFL also degrades p53 through stabilization of MDM2. (66, 67)
RFWD2 MTA1, p53, FoxO1 RFWD2 is also known as COP1. RFWD2 is an E3 ubiquitin ligase that ubiquitinates several proteins involved in the DNA damage response and apoptosis including MTA1, p53, and FoxO1. (68, 69, 70)
Rictor SGK1 Rictor interacts with Cullin1-Rbx1 to form an E3 ubiquitin ligase complex, and promotes ubiquitination and degradation of SGK1.  
RNF5 JAMP, paxillin RNF5 is also known as RMA5. RNF5 plays a role in ER-associated degradation of misfolded proteins and ER stress response through ubiquitination of JAMP. RNF5 also plays a role in cell motility and has been shown to ubiquitinate paxillin. (71, 72)
RNF8 H2A,H2AX RNF8 is a RING domain E3 ubiquitin ligase that plays a role in the repair of damaged chromosomes. RNF8 ubiquitinates Histone H2A and H2A.X at double-strand breaks (DSBs) which recruits 53BP1 and BRCA1 repair proteins. (73)
RNF19 SOD1 RNF19 is also known as Dorfin. Accumulation and aggregation of mutant SOD1 leads to ALS disease. RNF19 ubiquitinates mutant SOD1 protein, causing a decrease in neurotoxicity. (74)
RNF190   see MARCH-X  
RNF20 Histone H2B RNF20 is also known as BRE1. RNF20 is an E3 ubiquitin ligase that monoubiquitinates Histone H2B. H2B ubiquitination is associated with areas of active transcription. (75)
RNF34 Caspase-8, -10 RNF34 is also known as RFI. RNF34 inhibits death receptor mediated apoptosis through ubiquitination/degradation of caspase-8 and -10. (76)
RNF40 Histone H2B RNF40 is also known as BRE1-B. RNF40 forms a protein complex with RNF20 resulting in the ubiquitination of Histone H2B. H2B ubiquitination is associated with areas of active transcription. (77)
RNF125   RNF125 is also known as TRAC-1. RNF125 has been shown to positively regulate T cell activation. (78)
RNF128   RNF128 is also known as GRAIL. RNF128 promotes T cell anergy and may play a role in actin cytoskeletal organization in T cell/APC interactions. (79)
RNF138 TCF/LEF RNF138 is also known as NARF. RNF138 is associated with Nemo-like Kinase (NLK) and suppresses Wnt/β-Catenin signaling through ubiquitination/degradation of TCF/LEF. (80)
RNF168 H2A, H2A.X RNF168 is an E3 ubiquitin ligase that helps protect genome integrity by working together with RNF8 to ubiquitinate Histone H2A and H2A.X at DNA double-strand breaks (DSB). (81)
SCF/β-TrCP IκBα, Wee1, Cdc25A, β-Catenin SCF/β-TrCP is an E3 ubiquitin ligase complex composed of SCF (SKP1-CUL1-F-box protein) and the substrate recognition component, β-TrCP (also known as BTRC). SCF/β-TrCP mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction, and transcription. SCF/β-TrCP also regulates the stability of β-catenin and participates in Wnt signaling. (82, 83, 84, 85)
SCF/FBW7 Cyclin E, c-Myc, c-Jun SCF/FBW7 is an E3 ubiquitin ligase complex composed of SCF (SKP1-CUL1-F-box protein) and the substrate recognition component, FBW7. SCF/FBW7 mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction, and transcription. Target proteins for SCF/FBW7 include the phosphorylated forms of c-Myc, Cyclin E, Notch intracellular domain (NICD), and c-Jun. Defects in FBXW7 may be a cause of breast cancer. (86, 87, 88)
SCF/Skp2 p27, p21, Fox01 SCF/Skp2 is an E3 ubiquitin ligase complex composed of SCF (SKP1-CUL1-F-box protein) and the substrate recognition component, Skp2. SCF/Skp2 mediates the ubiquitination of proteins involved in cell cycle progression (specifically the G1/S transition), signal transduction and transcription. Target proteins for SCF/Skp2 include the phosphorylated forms of p27Kip1, p21Waf1/Cip1, and FoxO1. (89, 90)
SHPRH PCNA SHPRH is an E3 ubiquitin ligase that plays a role in DNA replication through ubiquitination of PCNA. PCNA ubiquitination prevents genomic instability from stalled replication forks after DNA damage. (91)
SIAH1 β-catenin, Bim, TRB3 SIAH1 is an E3 ubiquitin ligase that plays a role in inhibition of Wnt signaling through ubiquitination of β-catenin. SIAH1 has also been shown to promote apoptosis through upregulation of Bim, and to ubiquitinate the signaling adaptor protein TRB3. (92, 93, 94)
SIAH2 HIPK2, PHD1/3 SIAH2 is an E3 ubiquitin ligase that plays a role in hypoxia through ubiquitination and degradation of HIPK2. SIAH2 also ubiquitinates PHD1/3, which regulates levels of HIF-1α in response to hypoxia. (95, 96)
SMURF1 Smads SMURF1 is an E3 ubiquitin ligase that interacts with BMP pathway Smad effectors, leading to Smad protein ubiquitination and degradation. Smurf1 negatively regulates osteoblast differentiation and bone formation in vivo. (97, 98)
SMURF2 Smads, Mad2 SMURF2 is an E3 ubiquitin ligase that interacts with Smads from both the BMP and TGF-β pathways. SMURF2 also regulates the mitotic spindle checkpoint through ubiquitination of Mad2. (99, 100)
TOPORS p53, NKX3.1 TOPORS is an E3 ubiquitin ligase and a SUMO ligase. TOPORS ubiquitinates and sumoylates p53, which regulates p53 stability. TOPORS has also been shown to ubiquitinate the tumor supressor NKX3.1. (101, 102)
TRAF6 NEMO, Akt1 TRAF6 is an E3 ubiquitin ligase that functions as an adaptor protein in IL-1R, CD40, and TLR signaling. TRAF6 promotes NF-κB signaling through K63 polyubiquitination of IKK, resulting in IKK activation. TRAF6 has also been shown to ubiquitinate Akt1, causing its translocation to the cell membrane. (103, 104)
TRAF7   TRAF7 is an E3 ubiquitin ligase and SUMO ligase that functions as an adaptor protein in TNF Receptor and TLR signaling. TRAF7 has been shown to be capable of self-ubiquitination and plays a role in apoptosis via MEKK3-mediated activation of NF-κB. (105)
TRIM63 Troponin I, MyBP-C, MyLC1/2 TRIM63 is also known as Murf-1. TRIM63 is a muscle-specific E3 ubiquitin ligase whose expression is upregulated during muscle atrophy. TRIM63 has been shown to ubiquitinate several important muscle proteins including troponin I, MyBP-C, and MyLC1/2. (106)
UBE3B   UBE3B is an E3 ubiquitin ligase identified through sequence analysis. The specific substrates and cellular function of UBE3B is currently unknown. (107)
UBE3C   UBE3C is an E3 ubiquitin ligase also known as KIAA10. UBE3C is highly expressed in muscle and may interact with the transcriptional regulator TIP120B. (108)
UBR1   UBR1 is an E3 ubiquitin ligase responsible for proteasomal degradation of misfolded cytoplasmic proteins. UBR1 has also been shown to be a ubiquitin ligase of the N-end rule proteolytic pathway, which regulates degradation of short-lived proteins. (109, 110)
UBR2 Histone H2A UBR2 is an E3 ubiquitin ligase that has been shown to ubiquitinate histone H2A, resulting in transcriptional silencing. UBR2 is also part of the N-end rule proteolytic pathway. (111, 112)
UHRF2 PCNP UHRF2 is also known as NIRF. UHRF2 is a nuclear protein that may regulate cell cycle progression through association with Chk2. UHRF2 also ubiquitinates PCNP and has been shown to play a role in degradation of nuclear aggregates containing polyglutamine repeats. (113, 114, 115)
VHL HIF-1α VHL is the substrate recognition component of the ECV (Elongin B/C, Cullen-2, VHL) E3 ubiquitin ligase complex responsible for degradation of the transcription factor HIF-1α. Ubiquitination and degradation of HIF-1α takes place only during periods of normoxia, but not during hypoxia, thereby playing a central role in the regulation of gene expression by oxygen. (116)
WWP1 ErbB4 WWP1 is an E3 ubiquitin ligase commonly found to be overexpressed in breast cancer. WWP1 has been shown to ubiquitinate and degrade ErbB4. Interestingly, the WWP1 homolog in C. elegans was found to increase life expectancy in response to dietary restriction. (117, 118)
WWP2 Oct-4 WWP2 is an E3 ubiquitin ligase that has been shown to ubiquitinate/degrade the stem cell pluripotency factor Oct-4. WWP2 also ubiquitinates the transcription factor EGR2 to inhibit activation-induced T cell death. (119, 120)
ZNRF1   ZNRF1 is an E3 ubiquitin ligase highly expressed in neuronal cells. ZNRF1 is found in synaptic vesicle membranes and may regulate neuronal transmissions and plasticity. (121)

We would like to thank Prof. Wenyi Wei, Beth Israel Deaconess Medical Center, Harvard Medical School, for contributing to this table.


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