DegronMD - Q9C0C7(AMBRA1)

FUNCTION: Substrate-recognition component of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex involved in cell cycle control and autophagy (PubMed:20921139, PubMed:23524951, PubMed:24587252, PubMed:33854232, PubMed:33854235, PubMed:33854239, PubMed:32333458). The DCX(AMBRA1) complex specifically mediates the polyubiquitination of target proteins such as BECN1, CCND1, CCND2, CCND3, ELOC and ULK1 (PubMed:23524951, PubMed:33854232, PubMed:33854235, PubMed:33854239). Acts as an upstream master regulator of the transition from G1 to S cell phase: AMBRA1 specifically recognizes and binds phosphorylated cyclin-D (CCND1, CCND2 and CCND3), leading to cyclin-D ubiquitination by the DCX(AMBRA1) complex and subsequent degradation (PubMed:33854232, PubMed:33854235, PubMed:33854239). By controlling the transition from G1 to S phase and cyclin-D degradation, AMBRA1 acts as a tumor suppressor that promotes genomic integrity during DNA replication and counteracts developmental abnormalities and tumor growth (PubMed:33854232, PubMed:33854235, PubMed:33854239). AMBRA1 also regulates the cell cycle by promoting MYC dephosphorylation and degradation independently of the DCX(AMBRA1) complex: acts via interaction with the catalytic subunit of protein phosphatase 2A (PPP2CA), which enhances interaction between PPP2CA and MYC, leading to MYC dephosphorylation and degradation (PubMed:25803737, PubMed:25438055). Acts as a regulator of Cul5-RING (CRL5) E3 ubiquitin-protein ligase complexes by mediating ubiquitination and degradation of Elongin-C (ELOC) component of CRL5 complexes (PubMed:25499913, PubMed:30166453). Acts as a key regulator of autophagy by modulating the BECN1-PIK3C3 complex: controls protein turnover during neuronal development, and regulates normal cell survival and proliferation (PubMed:21358617). In normal conditions, AMBRA1 is tethered to the cytoskeleton via interaction with dyneins DYNLL1 and DYNLL2 (PubMed:20921139). Upon autophagy induction, AMBRA1 is released from the cytoskeletal docking site to induce autophagosome nucleation by mediating ubiquitination of proteins involved in autophagy (PubMed:20921139). The DCX(AMBRA1) complex mediates 'Lys-63'-linked ubiquitination of BECN1, increasing the association between BECN1 and PIK3C3 to promote PIK3C3 activity (By similarity). In collaboration with TRAF6, AMBRA1 mediates 'Lys-63'-linked ubiquitination of ULK1 following autophagy induction, promoting ULK1 stability and kinase activity (PubMed:23524951). Also activates ULK1 via interaction with TRIM32: TRIM32 stimulates ULK1 through unanchored 'Lys-63'-linked polyubiquitin chains (PubMed:31123703). Also acts as an activator of mitophagy via interaction with PRKN and LC3 proteins (MAP1LC3A, MAP1LC3B or MAP1LC3C); possibly by bringing damaged mitochondria onto autophagosomes (PubMed:21753002, PubMed:25215947). Also activates mitophagy by acting as a cofactor for HUWE1; acts by promoting HUWE1-mediated ubiquitination of MFN2 (PubMed:30217973). AMBRA1 is also involved in regulatory T-cells (Treg) differentiation by promoting FOXO3 dephosphorylation independently of the DCX(AMBRA1) complex: acts via interaction with PPP2CA, which enhances interaction between PPP2CA and FOXO3, leading to FOXO3 dephosphorylation and stabilization (PubMed:30513302). May act as a regulator of intracellular trafficking, regulating the localization of active PTK2/FAK and SRC (By similarity). Also involved in transcription regulation by acting as a scaffold for protein complexes at chromatin (By similarity). {ECO:0000250|UniProtKB:A2AH22, ECO:0000269|PubMed:20921139, ECO:0000269|PubMed:21358617, ECO:0000269|PubMed:21753002, ECO:0000269|PubMed:23524951, ECO:0000269|PubMed:24587252, ECO:0000269|PubMed:25215947, ECO:0000269|PubMed:25438055, ECO:0000269|PubMed:25499913, ECO:0000269|PubMed:25803737, ECO:0000269|PubMed:30166453, ECO:0000269|PubMed:30217973, ECO:0000269|PubMed:30513302, ECO:0000269|PubMed:31123703, ECO:0000269|PubMed:32333458, ECO:0000269|PubMed:33854232, ECO:0000269|PubMed:33854235, ECO:0000269|PubMed:33854239}. View more >>

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Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.E328K	TCGA-30-1855	OV	TCGA	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation blocking phosphorylation signal	0.6111
p.E328K	TCGA-30-1855	OV	TCGA	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation blocking phosphorylation signal	0.75
p.E328K	DO32666	OV	ICGC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation blocking phosphorylation signal	0.6111
p.E328K	DO32666	OV	ICGC	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation blocking phosphorylation signal	0.75
p.R380S	TCGA-A5-A0G2	UCEC	TCGA	VQSST	DEG_SPOP_SBC_1	374:378	Mutation rewiring degron network	0.2778
p.R380S	DO41235	UCEC	ICGC	VQSST	DEG_SPOP_SBC_1	374:378	Mutation rewiring degron network	0.2778
p.T374A	TCGA-AJ-A8CV	UCEC	TCGA	VQSST	DEG_SPOP_SBC_1	374:378	Mutation altering degron motif	0.7139
p.T374A	DO219766	UCEC	ICGC	VQSST	DEG_SPOP_SBC_1	374:378	Mutation altering degron motif	0.7139
p.R1202K	TCGA-AP-A05P	UCEC	TCGA	AHTSS	DEG_SPOP_SBC_1	1201:1205	Mutation altering degron motif	0.7237
p.E583D	TCGA-B5-A11E	UCEC	TCGA	NYSSGE	DEG_Kelch_Keap1_1	590:595	Mutation rewiring degron network	0.1389
p.E583D	DO41644	UCEC	ICGC	NYSSGE	DEG_Kelch_Keap1_1	590:595	Mutation rewiring degron network	0.1389
p.S1194N	TCGA-B5-A11H	UCEC	TCGA	AHTSS	DEG_SPOP_SBC_1	1201:1205	Mutation rewiring degron network	0.1389
p.R554M	TCGA-BG-A222	UCEC	TCGA	PTPHSS	DEG_SCF_FBW7_1	549:554	Mutation altering degron motif	0.8632
p.R554M	DO42977	UCEC	ICGC	PTPHSS	DEG_SCF_FBW7_1	549:554	Mutation altering degron motif	0.8632
p.S327A	TCGA-BR-4368	STAD	TCGA	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation altering degron motif	0.7588
p.S327A	DO38715	STAD	ICGC	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation altering degron motif	0.7588
p.G323V	TCGA-CG-5721	STAD	TCGA	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation altering degron motif	0.7532
p.G323V	TCGA-L5-A8NM	ESCA	TCGA	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation altering degron motif	0.7532
p.G323V	DO38192	STAD	ICGC	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation altering degron motif	0.7532
p.P550S	TCGA-D1-A0ZZ	UCEC	TCGA	PTPHSS	DEG_SCF_FBW7_1	549:554	Mutation altering degron motif	0.6752
p.P550S	DO43122	UCEC	ICGC	PTPHSS	DEG_SCF_FBW7_1	549:554	Mutation altering degron motif	0.6752
p.P550S	ACH-000786	Lymphoma	CCLE	PTPHSS	DEG_SCF_FBW7_1	549:554	Mutation altering degron motif	0.6752
p.P550S	ACH-000992	Head and Neck Cancer	CCLE	PTPHSS	DEG_SCF_FBW7_1	549:554	Mutation altering degron motif	0.6752
p.S310C	TCGA-D1-A16J	UCEC	TCGA	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation rewiring degron network	0.2778
p.S310C	DO43033	UCEC	ICGC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation rewiring degron network	0.2778
p.P313S	TCGA-D3-A1QB	SKCM	TCGA	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation altering degron motif	0.6752
p.P313S	DO47573	SKCM	ICGC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation altering degron motif	0.6752
p.R380M	TCGA-DI-A1BU	UCEC	TCGA	VQSST	DEG_SPOP_SBC_1	374:378	Mutation rewiring degron network	0.2778
p.R380M	DO42023	UCEC	ICGC	VQSST	DEG_SPOP_SBC_1	374:378	Mutation rewiring degron network	0.2778
p.E595Q	TCGA-DK-AA6P	BLCA	TCGA	NYSSGE	DEG_Kelch_Keap1_1	590:595	Mutation altering degron motif	0.6744
p.E595Q	DO219004	BLCA	ICGC	NYSSGE	DEG_Kelch_Keap1_1	590:595	Mutation altering degron motif	0.6744
p.G386E	TCGA-DU-6392	LGG	TCGA	VQSST	DEG_SPOP_SBC_1	374:378	Mutation rewiring degron network	0.1111
p.G386E	DO22237	LGG	ICGC	VQSST	DEG_SPOP_SBC_1	374:378	Mutation rewiring degron network	0.1111
p.E552K	TCGA-E7-A7XN	BLCA	TCGA	PTPHSS	DEG_SCF_FBW7_1	549:554	Mutation altering degron motif	0.7022
p.E552K	DO51878	BLCA	ICGC	PTPHSS	DEG_SCF_FBW7_1	549:554	Mutation altering degron motif	0.7022
p.D1197G	TCGA-FA-A86F	DLBC	TCGA	AHTSS	DEG_SPOP_SBC_1	1201:1205	Mutation rewiring degron network	0.2222
p.R331Q	TCGA-GN-A263	SKCM	TCGA	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation rewiring degron network	0.0833
p.R331Q	TCGA-GN-A263	SKCM	TCGA	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation rewiring degron network	0.2222
p.R331Q	DO37766	SKCM	ICGC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation rewiring degron network	0.0833
p.R331Q	DO37766	SKCM	ICGC	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation rewiring degron network	0.2222
p.R331Q	ACH-002222	Leukemia	CCLE	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation rewiring degron network	0.0833
p.R331Q	ACH-002222	Leukemia	CCLE	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation rewiring degron network	0.2222
p.R331Q	CTV-1	haematopoietic and lymphoid tissue	COSMIC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation rewiring degron network	0.0833
p.R331Q	CTV-1	haematopoietic and lymphoid tissue	COSMIC	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation rewiring degron network	0.2222
p.E328Q	TCGA-Q1-A73P	CESC	TCGA	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation blocking phosphorylation signal	0.6111
p.E328Q	TCGA-Q1-A73P	CESC	TCGA	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation blocking phosphorylation signal	0.75
p.E328Q	DO49983	CESC	ICGC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation blocking phosphorylation signal	0.6111
p.E328Q	DO49983	CESC	ICGC	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation blocking phosphorylation signal	0.75
p.R303H	TCGA-XK-AAIW	PRAD	TCGA	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation rewiring degron network	0.0833
p.R303H	DO51407	PRAD	ICGC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation rewiring degron network	0.0833
p.E583K	DO48457	BLCA	ICGC	NYSSGE	DEG_Kelch_Keap1_1	590:595	Mutation rewiring degron network	0.1389
p.S333C	DO1071	BRCA	ICGC	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation rewiring degron network	0.1667
p.Y373C	DO227987	COCA	ICGC	VQSST	DEG_SPOP_SBC_1	374:378	Mutation rewiring degron network	0.3056
p.S333F	DO234466	ESAD	ICGC	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation rewiring degron network	0.1667
p.R313H	DO13863	GBM	ICGC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation altering degron motif	0.7133
p.R313H	DO36556	READ	ICGC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation altering degron motif	0.7133
p.A388E	DO229035	LICA	ICGC	VQSST	DEG_SPOP_SBC_1	374:378	Mutation rewiring degron network	0.0556
p.L322I	DO26758	LUSC	ICGC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation altering degron motif	0.6063
p.L322I	DO26758	LUSC	ICGC	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation altering degron motif	0.6063
p.Q587H	DO232761	PBCA	ICGC	NYSSGE	DEG_Kelch_Keap1_1	590:595	Mutation rewiring degron network	0.25
p.L305F	DO37487	SKCM	ICGC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation rewiring degron network	0.1389
p.L310F	DO38123	SKCM	ICGC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation rewiring degron network	0.2778
p.S1202G	SIDM01307	Colorectal Carcinoma	GDSC	AHTSS	DEG_SPOP_SBC_1	1201:1205	Mutation altering degron motif	0.6993
p.S328N	SIDM00388	B-Cell Non-Hodgkin's Lymphoma	GDSC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation blocking phosphorylation signal	0.6111
p.S328N	SIDM00388	B-Cell Non-Hodgkin's Lymphoma	GDSC	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation blocking phosphorylation signal	0.75
p.S328N	ACH-002272	Lymphoma	CCLE	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation blocking phosphorylation signal	0.6111
p.S328N	ACH-002272	Lymphoma	CCLE	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation blocking phosphorylation signal	0.75
p.S328N	MHH-PREB-1	haematopoietic and lymphoid tissue	COSMIC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation blocking phosphorylation signal	0.6111
p.S328N	MHH-PREB-1	haematopoietic and lymphoid tissue	COSMIC	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation blocking phosphorylation signal	0.75
p.S315A	SIDM00845	Burkitt's Lymphoma	GDSC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation altering degron motif	0.7588
p.S315A	SIDM00461	Acute Myeloid Leukemia	GDSC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation altering degron motif	0.7588
p.S315A	SIDM01519	Head and Neck Carcinoma	GDSC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation altering degron motif	0.7588
p.S315A	Daudi	haematopoietic and lymphoid tissue	COSMIC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation altering degron motif	0.7588
p.G594C	SIDM00565	Oral Cavity Carcinoma	GDSC	NYSSGE	DEG_Kelch_Keap1_1	590:595	Mutation altering degron motif	0.76
p.G594C	OSC-20	upper aerodigestive tract	COSMIC	NYSSGE	DEG_Kelch_Keap1_1	590:595	Mutation altering degron motif	0.76
p.Y591C	SIDM00938	Breast Carcinoma	GDSC	NYSSGE	DEG_Kelch_Keap1_1	590:595	Mutation altering degron motif	0.5976
p.Y591C	SIDM00654	Small Cell Lung Carcinoma	GDSC	NYSSGE	DEG_Kelch_Keap1_1	590:595	Mutation altering degron motif	0.5976
p.N1237Y	SIDM00659	Glioblastoma	GDSC	PGTPGRE	DEG_SCF_FBW7_2	1236:1242	Mutation altering degron motif	0.7059
p.N1237Y	M059J	central nervous system	COSMIC	PGTPGRE	DEG_SCF_FBW7_2	1236:1242	Mutation altering degron motif	0.7059
p.R1232M	SIDM01007	T-Lymphoblastic Leukemia	GDSC	PGTPGRE	DEG_SCF_FBW7_2	1236:1242	Mutation rewiring degron network	0.2222
p.R1232M	KARPAS-45	haematopoietic and lymphoid tissue	COSMIC	PGTPGRE	DEG_SCF_FBW7_2	1236:1242	Mutation rewiring degron network	0.2222
p.T1207A	SIDM00661	B-Cell Non-Hodgkin's Lymphoma	GDSC	AHTSS	DEG_SPOP_SBC_1	1201:1205	Mutation rewiring degron network	0.2778
p.T1207A	HT	haematopoietic and lymphoid tissue	COSMIC	AHTSS	DEG_SPOP_SBC_1	1201:1205	Mutation rewiring degron network	0.2778
p.R318Q	SIDM00301	Pancreatic Carcinoma	GDSC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation altering degron motif	0.6218
p.R318Q	SIDM01336	Glioblastoma	GDSC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation altering degron motif	0.6218
p.R318Q	SIDM01442	Glioma	GDSC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation altering degron motif	0.6218
p.R318Q	KP-4	pancreas	COSMIC	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation altering degron motif	0.6218
p.A336T	SIDM01032	Esophageal Squamous Cell Carcinoma	GDSC	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation rewiring degron network	0.0833
p.A336T	SIDM01551	Gastric Carcinoma	GDSC	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation rewiring degron network	0.0833
p.A336T	ACH-000485	Gastric Cancer	CCLE	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation rewiring degron network	0.0833
p.A336T	ACH-000823	Esophageal Cancer	CCLE	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation rewiring degron network	0.0833
p.R367Q	SIDM01617	Endometrial Carcinoma	GDSC	VQSST	DEG_SPOP_SBC_1	374:378	Mutation rewiring degron network	0.1389
p.S377N	SIDM01729	Endometrial Carcinoma	GDSC	VQSST	DEG_SPOP_SBC_1	374:378	Mutation altering degron motif	0.7069
p.G379E	ACH-000564	Myeloma	CCLE	VQSST	DEG_SPOP_SBC_1	374:378	Mutation rewiring degron network	0.3056
p.A384S	ACH-000786	Lymphoma	CCLE	VQSST	DEG_SPOP_SBC_1	374:378	Mutation rewiring degron network	0.1667
p.A384S	ACH-000992	Head and Neck Cancer	CCLE	VQSST	DEG_SPOP_SBC_1	374:378	Mutation rewiring degron network	0.1667
p.A384S	S-117	soft tissue	COSMIC	VQSST	DEG_SPOP_SBC_1	374:378	Mutation rewiring degron network	0.1667
p.A384S	Daudi	haematopoietic and lymphoid tissue	COSMIC	VQSST	DEG_SPOP_SBC_1	374:378	Mutation rewiring degron network	0.1667
p.A384S	OCI-AML5	haematopoietic and lymphoid tissue	COSMIC	VQSST	DEG_SPOP_SBC_1	374:378	Mutation rewiring degron network	0.1667
p.H317Y	ACH-000921	Lung Cancer	CCLE	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation altering degron motif	0.7229
p.N1207Y	ACH-001118	Brain Cancer	CCLE	AHTSS	DEG_SPOP_SBC_1	1201:1205	Mutation rewiring degron network	0.2778
p.N1207Y	M059J	central nervous system	COSMIC	AHTSS	DEG_SPOP_SBC_1	1201:1205	Mutation rewiring degron network	0.2778
p.P383L	ACH-001399	Colon/Colorectal Cancer	CCLE	VQSST	DEG_SPOP_SBC_1	374:378	Mutation rewiring degron network	0.1944
p.P383L	SW626	ovary	COSMIC	VQSST	DEG_SPOP_SBC_1	374:378	Mutation rewiring degron network	0.1944
p.G326R	ACH-001999	Pancreatic Cancer	CCLE	LLPHQD	LIG_APCC_ABBA_1	322:327	Mutation altering degron motif	0.7568
p.G307A	ACH-002024	Colon/Colorectal Cancer	CCLE	SRCSGTRVPSL	DEG_COP1_1	312:322	Mutation rewiring degron network	0.1944
p.R1202M	ACH-002256	Leukemia	CCLE	AHTSS	DEG_SPOP_SBC_1	1201:1205	Mutation altering degron motif	0.8632
p.R1202M	KARPAS-45	haematopoietic and lymphoid tissue	COSMIC	AHTSS	DEG_SPOP_SBC_1	1201:1205	Mutation altering degron motif	0.8632
p.E1235G	SW1271	lung	COSMIC	PGTPGRE	DEG_SCF_FBW7_2	1236:1242	Mutation rewiring degron network	0.3056
p.A1200S	NCI-H2342	lung	COSMIC	AHTSS	DEG_SPOP_SBC_1	1201:1205	Mutation rewiring degron network	0.3056
p.L1215F	SNU-C5	large intestine	COSMIC	AHTSS	DEG_SPOP_SBC_1	1201:1205	Mutation rewiring degron network	0.0556
p.P1195L	KARPAS-45	haematopoietic and lymphoid tissue	COSMIC	AHTSS	DEG_SPOP_SBC_1	1201:1205	Mutation rewiring degron network	0.1667
p.T1238A	HT	haematopoietic and lymphoid tissue	COSMIC	PGTPGRE	DEG_SCF_FBW7_2	1236:1242	Mutation altering degron motif	0.825
p.E1204G	SW1271	lung	COSMIC	AHTSS	DEG_SPOP_SBC_1	1201:1205	Mutation altering degron motif	0.7199
p.P1226L	KARPAS-45	haematopoietic and lymphoid tissue	COSMIC	PGTPGRE	DEG_SCF_FBW7_2	1236:1242	Mutation rewiring degron network	0.0556

Kaplan plot for AMBRA1 in

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*NOTE: the Kaplan plots were collected from OncoLnc

DegronMD: protein-targeted degradation, mutation and drug response to degrons

AMBRA1

UniProt ID: Q9C0C7

Entrez ID: 55626

Protein name: Activating molecule in BECN1-regulated autophagy protein 1 (DDB1- and CUL4-associated factor 3)

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for AMBRA1 in