DegronMD - Q92673(SORL1)

FUNCTION: Sorting receptor that directs several proteins to their correct location within the cell (Probable). Along with AP-1 complex, involved Golgi apparatus - endosome sorting (PubMed:17646382). Sorting receptor for APP, regulating its intracellular trafficking and processing into amyloidogenic-beta peptides. Retains APP in the trans-Golgi network, hence preventing its transit through late endosomes where amyloid beta peptides Abeta40 and Abeta42 are generated (PubMed:16174740, PubMed:16407538, PubMed:17855360, PubMed:24523320). May also sort newly produced amyloid-beta peptides to lysosomes for catabolism (PubMed:24523320). Does not affect APP trafficking from the endoplasmic reticulum to Golgi compartments (PubMed:17855360). Sorting receptor for the BDNF receptor NTRK2/TRKB that facilitates NTRK2 trafficking between synaptic plasma membranes, postsynaptic densities and cell soma, hence positively regulates BDNF signaling by controlling the intracellular location of its receptor (PubMed:23977241). Sorting receptor for GDNF that promotes GDNF regulated, but not constitutive secretion (PubMed:21994944). Sorting receptor for the GDNF-GFRA1 complex, directing it from the cell surface to endosomes. GDNF is then targeted to lysosomes and degraded, while its receptor GFRA1 recycles back to the cell membrane, resulting in a GDNF clearance pathway. The SORL1-GFRA1 complex further targets RET for endocytosis, but not for degradation, affecting GDNF-induced neurotrophic activities (PubMed:23333276). Sorting receptor for ERBB2/HER2. Regulates ERBB2 subcellular distribution by promoting its recycling after internalization from endosomes back to the plasma membrane, hence stimulating phosphoinositide 3-kinase (PI3K)-dependent ERBB2 signaling. In ERBB2-dependent cancer cells, promotes cell proliferation (PubMed:31138794). Sorting receptor for lipoprotein lipase LPL. Promotes LPL localization to endosomes and later to the lysosomes, leading to degradation of newly synthesized LPL (PubMed:21385844). Potential sorting receptor for APOA5, inducing APOA5 internalization to early endosomes, then to late endosomes, wherefrom a portion is sent to lysosomes and degradation, another portion is sorted to the trans-Golgi network (PubMed:18603531). Sorting receptor for the insulin receptor INSR. Promotes recycling of internalized INSR via the Golgi apparatus back to the cell surface, thereby preventing lysosomal INSR catabolism, increasing INSR cell surface expression and strengthening insulin signal reception in adipose tissue. Does not affect INSR internalization (PubMed:27322061). Plays a role in renal ion homeostasis, controlling the phospho-regulation of SLC12A1/NKCC2 by STK39/SPAK kinase and PPP3CB/calcineurin A beta phosphatase, possibly through intracellular sorting of STK39 and PPP3CB (By similarity). Stimulates, via the N-terminal ectodomain, the proliferation and migration of smooth muscle cells, possibly by increasing cell surface expression of the urokinase receptor uPAR/PLAUR. This may promote extracellular matrix proteolysis and hence facilitate cell migration (PubMed:14764453). By acting on the migration of intimal smooth muscle cells, may accelerate intimal thickening following vascular injury (PubMed:14764453). Promotes adhesion of monocytes (PubMed:23486467). Stimulates proliferation and migration of monocytes/macrophages (By similarity). Through its action on intimal smooth muscle cells and macrophages, may accelerate intimal thickening and macrophage foam cell formation in the process of atherosclerosis (By similarity). Regulates hypoxia-enhanced adhesion of hematopoietic stem and progenitor cells to the bone marrow stromal cells via a PLAUR-mediated pathway. This function is mediated by the N-terminal ectodomain (PubMed:23486467). Metabolic regulator, which functions to maintain the adequate balance between lipid storage and oxidation in response to changing environmental conditions, such as temperature and diet. The N-terminal ectodomain negatively regulates adipose tissue energy expenditure, acting through the inhibition the BMP/Smad pathway (By similarity). May regulate signaling by the heterodimeric neurotrophic cytokine CLCF1-CRLF1 bound to the CNTFR receptor by promoting the endocytosis of the tripartite complex CLCF1-CRLF1-CNTFR and lysosomal degradation (PubMed:26858303). May regulate IL6 signaling, decreasing cis signaling, possibly by interfering with IL6-binding to membrane-bound IL6R, while up-regulating trans signaling via soluble IL6R (PubMed:28265003). {ECO:0000250|UniProtKB:O88307, ECO:0000269|PubMed:14764453, ECO:0000269|PubMed:16174740, ECO:0000269|PubMed:16407538, ECO:0000269|PubMed:17646382, ECO:0000269|PubMed:17855360, ECO:0000269|PubMed:18603531, ECO:0000269|PubMed:21385844, ECO:0000269|PubMed:21994944, ECO:0000269|PubMed:23333276, ECO:0000269|PubMed:23486467, ECO:0000269|PubMed:23977241, ECO:0000269|PubMed:24523320, ECO:0000269|PubMed:26858303, ECO:0000269|PubMed:27322061, ECO:0000269|PubMed:28265003, ECO:0000269|PubMed:31138794, ECO:0000305}. View more >>

GO - Biological processes (BP): adaptive thermogenesis [GO:1990845]; cell migration [GO:0016477]; cell population proliferation [GO:0008283]; diet induced thermogenesis [GO:0002024]; insulin receptor recycling [GO:0038020]; negative regulation of amyloid-beta formation [GO:1902430]; negative regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process [GO:1902960]; negative regulation of BMP signaling pathway [GO:0030514]; negative regulation of MAP kinase activity [GO:0043407]; negative regulation of metalloendopeptidase activity involved in amyloid precursor protein catabolic process [GO:1902963]; negative regulation of neurofibrillary tangle assembly [GO:1902997]; negative regulation of neurogenesis [GO:0050768]; negative regulation of neuron death [GO:1901215]; negative regulation of protein binding [GO:0032091]; negative regulation of protein-containing complex assembly [GO:0031333]; negative regulation of tau-protein kinase activity [GO:1902948]; negative regulation of triglyceride catabolic process [GO:0010897]; neuropeptide signaling pathway [GO:0007218]; positive regulation of adipose tissue development [GO:1904179]; positive regulation of choline O-acetyltransferase activity [GO:1902771]; positive regulation of early endosome to recycling endosome transport [GO:1902955]; positive regulation of endocytic recycling [GO:2001137]; positive regulation of ER to Golgi vesicle-mediated transport [GO:1902953]; positive regulation of glial cell-derived neurotrophic factor production [GO:1900168]; positive regulation of insulin receptor signaling pathway [GO:0046628]; positive regulation of protein catabolic process [GO:0045732]; positive regulation of protein exit from endoplasmic reticulum [GO:0070863]; positive regulation of protein localization to early endosome [GO:1902966]; post-Golgi vesicle-mediated transport [GO:0006892]; protein localization to Golgi apparatus [GO:0034067]; protein maturation [GO:0051604]; protein retention in Golgi apparatus [GO:0045053]; protein targeting [GO:0006605]; protein targeting to lysosome [GO:0006622]; receptor-mediated endocytosis [GO:0006898]; regulation of smooth muscle cell migration [GO:0014910] View more >>

GO - Molecular function (MF): View more >>

GO - Cellular component (CC): View more >>

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Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.G585D	TCGA-BR-8361	STAD	TCGA	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.1389
p.G585D	TCGA-EB-A41A	SKCM	TCGA	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.1389
p.G585D	DO37429	SKCM	ICGC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.1389
p.G585D	DO48032	STAD	ICGC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.1389
p.T565P	TCGA-FA-A82F	DLBC	TCGA	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.1389
p.T565P	DO219891	DLBC	ICGC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.1389
p.L586I	TCGA-HU-8602	STAD	TCGA	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.1111
p.L586I	DO47829	STAD	ICGC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.1111
p.R575H	DO8400	COAD	ICGC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation altering degron motif	0.8244
p.R575H	DO47769	STAD	ICGC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation altering degron motif	0.8244
p.R575C	DO222755	COCA	ICGC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation altering degron motif	0.8301
p.V583L	DO229031	LICA	ICGC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.1944
p.G576V	DO229031	LICA	ICGC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation altering degron motif	0.7532
p.R575L	DO229036	LICA	ICGC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation altering degron motif	0.8428
p.G578E	DO220886	MELA	ICGC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation altering degron motif	0.7199
p.G578E	DO51283	SKCM	ICGC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation altering degron motif	0.7199
p.G576R	DO37406	SKCM	ICGC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation altering degron motif	0.7568
p.D582N	DO50288	SKCM	ICGC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.2222
p.V567I	DO47833	STAD	ICGC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.1944
p.V567I	HCT-15	large intestine	COSMIC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.1944
p.F574S	DO229272	THCA	ICGC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation altering degron motif	0.6871
p.G568E	SIDM00422	Hodgkin's Lymphoma	GDSC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.2222
p.G568E	ACH-001203	Lymphoma	CCLE	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.2222
p.G568E	SUP-HD1	haematopoietic and lymphoid tissue	COSMIC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.2222
p.S564R	SIDM00400	B-Cell Non-Hodgkin's Lymphoma	GDSC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.1111
p.S564R	ACH-002392	Lymphoma	CCLE	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.1111
p.S564R	SC-1	haematopoietic and lymphoid tissue	COSMIC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.1111
p.I579T	ACH-002196	Lung Cancer	CCLE	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.3056
p.I579T	SBC-1	lung	COSMIC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.3056
p.D577A	HLE	liver	COSMIC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation altering degron motif	0.7793
p.D577A	SCC-3	haematopoietic and lymphoid tissue	COSMIC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation altering degron motif	0.7793
p.K578M	EC-GI-10	oesophagus	COSMIC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation altering degron motif	0.8062
p.K578M	HAL-01	haematopoietic and lymphoid tissue	COSMIC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation altering degron motif	0.8062
p.K578M	OSC-20	upper aerodigestive tract	COSMIC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation altering degron motif	0.8062
p.P570L	SNU-1040	large intestine	COSMIC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.2778
p.P570S	MZ7-mel	skin	COSMIC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.2778
p.K585N	HT-115	large intestine	COSMIC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation rewiring degron network	0.1389
p.G576E	ChaGo-K-1	lung	COSMIC	KTFIFSE	LIG_APCC_ABBAyCdc20_2	572:578	Mutation altering degron motif	0.7199

Kaplan plot for SORL1 in

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*NOTE: the Kaplan plots were collected from OncoLnc

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

SORL1

UniProt ID: Q92673

Entrez ID: 6653

Protein name: Sortilin-related receptor (Low-density lipoprotein receptor relative with 11 ligand-binding repeats) (LDLR relative with 11 ligand-binding repeats) (LR11) (SorLA-1) (Sorting protein-related receptor containing LDLR class A repeats) (SorLA)

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for SORL1 in