UniProt functional annotation for P98158



	UniProt functional annotation for P98158

UniProt code: P98158.

Organism: Rattus norvegicus (Rat).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Rattus.

Function: Multiligand endocytic receptor. Acts together with CUBN to mediate endocytosis of high-density lipoproteins (By similarity). Mediates receptor-mediated uptake of polybasic drugs such as aprotinin, aminoglycosides and polymyxin B (PubMed:7544804, PubMed:19202329). In the kidney, mediates the tubular uptake and clearance of leptin (By similarity). Also mediates transport of leptin across the blood-brain barrier through endocytosis at the choroid plexus epithelium (PubMed:17324488). Endocytosis of leptin in neuronal cells is required for hypothalamic leptin signaling and leptin-mediated regulation of feeding and body weight (By similarity). Mediates endocytosis and subsequent lysosomal degradation of CST3 in kidney proximal tubule cells (PubMed:17462596). Mediates renal uptake of 25-hydroxyvitamin D3 in complex with the vitamin D3 transporter GC/DBP (By similarity). Mediates renal uptake of metallothionein-bound heavy metals (PubMed:15126248). Together with CUBN, mediates renal reabsorption of myoglobin (PubMed:12724130). Mediates renal uptake and subsequent lysosomal degradation of APOM (PubMed:16099815). Plays a role in kidney selenium homeostasis by mediating renal endocytosis of selenoprotein SEPP1 (By similarity). Mediates renal uptake of the antiapoptotic protein BIRC5/survivin which may be important for functional integrity of the kidney (By similarity). Mediates renal uptake of matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1 (PubMed:28659595). Mediates endocytosis of Sonic hedgehog protein N-product (ShhN), the active product of SHH (PubMed:11964399, PubMed:16801528). Also mediates ShhN transcytosis (PubMed:16801528). In the embryonic neuroepithelium, mediates endocytic uptake and degradation of BMP4, is required for correct SHH localization in the ventral neural tube and plays a role in patterning of the ventral telencephalon (By similarity). Required at the onset of neurulation to sequester SHH on the apical surface of neuroepithelial cells of the rostral diencephalon ventral midline and to control PTCH1-dependent uptake and intracellular trafficking of SHH (By similarity). During neurulation, required in neuroepithelial cells for uptake of folate bound to the folate receptor FOLR1 which is necessary for neural tube closure (By similarity). In the adult brain, negatively regulates BMP signaling in the subependymal zone which enables neurogenesis to proceed (By similarity). In astrocytes, mediates endocytosis of ALB which is required for the synthesis of the neurotrophic factor oleic acid (PubMed:18466341). Involved in neurite branching (By similarity). During optic nerve development, required for SHH-mediated migration and proliferation of oligodendrocyte precursor cells (By similarity). Mediates endocytic uptake and clearance of SHH in the retinal margin which protects retinal progenitor cells from mitogenic stimuli and keeps them quiescent (By similarity). Plays a role in reproductive organ development by mediating uptake in reproductive tissues of androgen and estrogen bound to the sex hormone binding protein SHBG (PubMed:16143106). Mediates endocytosis of angiotensin-2 (PubMed:15467006). Also mediates endocytosis of angiotensin 1-7 (PubMed:16380466). Binds to the complex composed of beta-amyloid protein 40 and CLU/APOJ and mediates its endocytosis and lysosomal degradation (By similarity). Required for embryonic heart development (By similarity). Required for normal hearing, possibly through interaction with estrogen in the inner ear (PubMed:17846082). {ECO:0000250|UniProtKB:A2ARV4, ECO:0000250|UniProtKB:C0HL13, ECO:0000250|UniProtKB:P98164, ECO:0000269|PubMed:11964399, ECO:0000269|PubMed:12724130, ECO:0000269|PubMed:15126248, ECO:0000269|PubMed:15467006, ECO:0000269|PubMed:16099815, ECO:0000269|PubMed:16143106, ECO:0000269|PubMed:16380466, ECO:0000269|PubMed:16801528, ECO:0000269|PubMed:17324488, ECO:0000269|PubMed:17462596, ECO:0000269|PubMed:17846082, ECO:0000269|PubMed:18466341, ECO:0000269|PubMed:19202329, ECO:0000269|PubMed:28659595, ECO:0000269|PubMed:7544804}.

Subunit: Binds plasminogen, extracellular matrix components, plasminogen activator-plasminogen activator inhibitor type I complex, apolipoprotein E-enriched beta-VLDL, lipoprotein lipase, lactoferrin, CLU/clusterin and calcium. Forms a multimeric complex together with LRPAP1 (PubMed:1400426). Interacts (via PxLPxI/L motif) with ANKRA2 (via ankyrin repeats) (PubMed:22649097). Interacts with LRP2BP. Interacts (via NPXY motif) with DAB2; the interaction is not affected by tyrosine phosphorylation of the NPXY motif (By similarity). Interacts with MB (PubMed:12724130). Interacts with BMP4 (By similarity). Interacts with the Sonic hedgehog protein N-product which is the active product of SHH (By similarity). Interacts with CST3 in a calcium-dependent manner (PubMed:17462596). Interacts with the vitamin- D binding protein GC/DBP (By similarity). Interacts with sex hormone- binding protein SHBG (PubMed:16143106). Interacts with angiotensin-2 (By similarity). Also interacts with angiotensin 1-7 (By similarity). Interacts with APOM (By similarity). Interacts with selenoprotein SEPP1 (By similarity). Interacts with LEP (PubMed:17324488). Interacts with ALB (PubMed:18466341). Interacts with the antiapoptotic protein BIRC5/survivin (By similarity). Interacts with matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1 (PubMed:28659595). In neurons, forms a trimeric complex with APP and APPB1/FE65 (By similarity). Interacts with LDLRAP1/ARH; mediates trafficking of LRP2 to the endocytic recycling compartment (PubMed:23836931). Does not interact with beta-amyloid protein 40 alone but interacts with the complex composed of beta-amyloid protein 40 and CLU/APOJ (By similarity). Interacts with MDK (By similarity). {ECO:0000250|UniProtKB:A2ARV4, ECO:0000250|UniProtKB:C0HL13, ECO:0000250|UniProtKB:P98164, ECO:0000269|PubMed:12724130, ECO:0000269|PubMed:1400426, ECO:0000269|PubMed:15467006, ECO:0000269|PubMed:16143106, ECO:0000269|PubMed:17462596, ECO:0000269|PubMed:18466341, ECO:0000269|PubMed:22649097, ECO:0000269|PubMed:23836931, ECO:0000269|PubMed:28659595}.

Subcellular location: Apical cell membrane {ECO:0000269|PubMed:12519751, ECO:0000269|PubMed:18466341, ECO:0000269|PubMed:19202329, ECO:0000269|PubMed:6752952}; Single-pass type I membrane protein {ECO:0000255}. Endosome lumen {ECO:0000269|PubMed:17063000}. Membrane, clathrin-coated pit {ECO:0000250|UniProtKB:A2ARV4}. Cell projection, dendrite {ECO:0000250|UniProtKB:A2ARV4}. Cell projection, axon {ECO:0000250|UniProtKB:A2ARV4}. Note=Localizes to brush border membranes in the kidney (PubMed:6752952, PubMed:12724130). In the endolymphatic sac of the inner ear, located in the lumen of endosomes as a soluble form (PubMed:17063000). {ECO:0000269|PubMed:12724130, ECO:0000269|PubMed:6752952}.

Tissue specificity: In the inner ear, expressed in the lumen of the endolymphatic sac where it localizes to macrophage-like cells as well as to mitochondria-rich and ribosome-rich epithelial cells (at protein level) (PubMed:17063000). In the inner ear, expressed in marginal cells of the stria vascularis, epithelial cells at the spiral prominence, epithelial cells of Reissner's membrane facing the cochlear duct, and Kolliker's organ (at protein level) (PubMed:19202329). Expressed in the choroid plexus epithelium in the brain (at protein level) (PubMed:17324488). In the brain, also expressed in astrocytes (at protein level) (PubMed:18466341). Expression also detected in epithelial cells of the kidney glomerulus and proximal tubule, lung, epididymis and yolk sac (PubMed:7510321). {ECO:0000269|PubMed:17063000, ECO:0000269|PubMed:17324488, ECO:0000269|PubMed:18466341, ECO:0000269|PubMed:19202329, ECO:0000269|PubMed:7510321}.

Developmental stage: In the brain, expression is high after birth and gradually decreases from postnatal day 4 until the end of the first postnatal week. {ECO:0000269|PubMed:18466341}.

Domain: Two overlapping PxLPxI/L motifs mediate interaction with ankyrin repeats of ANKRA2. {ECO:0000269|PubMed:22649097}.

Domain: The cytoplasmic domain is required for sorting to the apical cell membrane. {ECO:0000269|PubMed:12519751}.

Ptm: A fraction undergoes proteolytic cleavage of the extracellular domain at the cell membrane to generate a cytoplasmic tail fragment. This is internalized into the early endosome from where it trafficks in an LDLRAP1/ARH-dependent manner to the endocytic recycling compartment (ERC). In the ERC, it is further cleaved by gamma-secretase to release a fragment which translocates to the nucleus and mediates transcriptional repression. {ECO:0000269|PubMed:23836931}.

Ptm: N-glycosylation is required for ligand binding. {ECO:0000250|UniProtKB:A2ARV4}.

Similarity: Belongs to the LDLR family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Rattus norvegicus (Rat).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Rattus.



Function:		Multiligand endocytic receptor. Acts together with CUBN to mediate endocytosis of high-density lipoproteins (By similarity). Mediates receptor-mediated uptake of polybasic drugs such as aprotinin, aminoglycosides and polymyxin B (PubMed:7544804, PubMed:19202329). In the kidney, mediates the tubular uptake and clearance of leptin (By similarity). Also mediates transport of leptin across the blood-brain barrier through endocytosis at the choroid plexus epithelium (PubMed:17324488). Endocytosis of leptin in neuronal cells is required for hypothalamic leptin signaling and leptin-mediated regulation of feeding and body weight (By similarity). Mediates endocytosis and subsequent lysosomal degradation of CST3 in kidney proximal tubule cells (PubMed:17462596). Mediates renal uptake of 25-hydroxyvitamin D3 in complex with the vitamin D3 transporter GC/DBP (By similarity). Mediates renal uptake of metallothionein-bound heavy metals (PubMed:15126248). Together with CUBN, mediates renal reabsorption of myoglobin (PubMed:12724130). Mediates renal uptake and subsequent lysosomal degradation of APOM (PubMed:16099815). Plays a role in kidney selenium homeostasis by mediating renal endocytosis of selenoprotein SEPP1 (By similarity). Mediates renal uptake of the antiapoptotic protein BIRC5/survivin which may be important for functional integrity of the kidney (By similarity). Mediates renal uptake of matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1 (PubMed:28659595). Mediates endocytosis of Sonic hedgehog protein N-product (ShhN), the active product of SHH (PubMed:11964399, PubMed:16801528). Also mediates ShhN transcytosis (PubMed:16801528). In the embryonic neuroepithelium, mediates endocytic uptake and degradation of BMP4, is required for correct SHH localization in the ventral neural tube and plays a role in patterning of the ventral telencephalon (By similarity). Required at the onset of neurulation to sequester SHH on the apical surface of neuroepithelial cells of the rostral diencephalon ventral midline and to control PTCH1-dependent uptake and intracellular trafficking of SHH (By similarity). During neurulation, required in neuroepithelial cells for uptake of folate bound to the folate receptor FOLR1 which is necessary for neural tube closure (By similarity). In the adult brain, negatively regulates BMP signaling in the subependymal zone which enables neurogenesis to proceed (By similarity). In astrocytes, mediates endocytosis of ALB which is required for the synthesis of the neurotrophic factor oleic acid (PubMed:18466341). Involved in neurite branching (By similarity). During optic nerve development, required for SHH-mediated migration and proliferation of oligodendrocyte precursor cells (By similarity). Mediates endocytic uptake and clearance of SHH in the retinal margin which protects retinal progenitor cells from mitogenic stimuli and keeps them quiescent (By similarity). Plays a role in reproductive organ development by mediating uptake in reproductive tissues of androgen and estrogen bound to the sex hormone binding protein SHBG (PubMed:16143106). Mediates endocytosis of angiotensin-2 (PubMed:15467006). Also mediates endocytosis of angiotensin 1-7 (PubMed:16380466). Binds to the complex composed of beta-amyloid protein 40 and CLU/APOJ and mediates its endocytosis and lysosomal degradation (By similarity). Required for embryonic heart development (By similarity). Required for normal hearing, possibly through interaction with estrogen in the inner ear (PubMed:17846082). {ECO:0000250\|UniProtKB:A2ARV4, ECO:0000250\|UniProtKB:C0HL13, ECO:0000250\|UniProtKB:P98164, ECO:0000269\|PubMed:11964399, ECO:0000269\|PubMed:12724130, ECO:0000269\|PubMed:15126248, ECO:0000269\|PubMed:15467006, ECO:0000269\|PubMed:16099815, ECO:0000269\|PubMed:16143106, ECO:0000269\|PubMed:16380466, ECO:0000269\|PubMed:16801528, ECO:0000269\|PubMed:17324488, ECO:0000269\|PubMed:17462596, ECO:0000269\|PubMed:17846082, ECO:0000269\|PubMed:18466341, ECO:0000269\|PubMed:19202329, ECO:0000269\|PubMed:28659595, ECO:0000269\|PubMed:7544804}.


Subunit:		Binds plasminogen, extracellular matrix components, plasminogen activator-plasminogen activator inhibitor type I complex, apolipoprotein E-enriched beta-VLDL, lipoprotein lipase, lactoferrin, CLU/clusterin and calcium. Forms a multimeric complex together with LRPAP1 (PubMed:1400426). Interacts (via PxLPxI/L motif) with ANKRA2 (via ankyrin repeats) (PubMed:22649097). Interacts with LRP2BP. Interacts (via NPXY motif) with DAB2; the interaction is not affected by tyrosine phosphorylation of the NPXY motif (By similarity). Interacts with MB (PubMed:12724130). Interacts with BMP4 (By similarity). Interacts with the Sonic hedgehog protein N-product which is the active product of SHH (By similarity). Interacts with CST3 in a calcium-dependent manner (PubMed:17462596). Interacts with the vitamin- D binding protein GC/DBP (By similarity). Interacts with sex hormone- binding protein SHBG (PubMed:16143106). Interacts with angiotensin-2 (By similarity). Also interacts with angiotensin 1-7 (By similarity). Interacts with APOM (By similarity). Interacts with selenoprotein SEPP1 (By similarity). Interacts with LEP (PubMed:17324488). Interacts with ALB (PubMed:18466341). Interacts with the antiapoptotic protein BIRC5/survivin (By similarity). Interacts with matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1 (PubMed:28659595). In neurons, forms a trimeric complex with APP and APPB1/FE65 (By similarity). Interacts with LDLRAP1/ARH; mediates trafficking of LRP2 to the endocytic recycling compartment (PubMed:23836931). Does not interact with beta-amyloid protein 40 alone but interacts with the complex composed of beta-amyloid protein 40 and CLU/APOJ (By similarity). Interacts with MDK (By similarity). {ECO:0000250\|UniProtKB:A2ARV4, ECO:0000250\|UniProtKB:C0HL13, ECO:0000250\|UniProtKB:P98164, ECO:0000269\|PubMed:12724130, ECO:0000269\|PubMed:1400426, ECO:0000269\|PubMed:15467006, ECO:0000269\|PubMed:16143106, ECO:0000269\|PubMed:17462596, ECO:0000269\|PubMed:18466341, ECO:0000269\|PubMed:22649097, ECO:0000269\|PubMed:23836931, ECO:0000269\|PubMed:28659595}.
Subcellular location:		Apical cell membrane {ECO:0000269\|PubMed:12519751, ECO:0000269\|PubMed:18466341, ECO:0000269\|PubMed:19202329, ECO:0000269\|PubMed:6752952}; Single-pass type I membrane protein {ECO:0000255}. Endosome lumen {ECO:0000269\|PubMed:17063000}. Membrane, clathrin-coated pit {ECO:0000250\|UniProtKB:A2ARV4}. Cell projection, dendrite {ECO:0000250\|UniProtKB:A2ARV4}. Cell projection, axon {ECO:0000250\|UniProtKB:A2ARV4}. Note=Localizes to brush border membranes in the kidney (PubMed:6752952, PubMed:12724130). In the endolymphatic sac of the inner ear, located in the lumen of endosomes as a soluble form (PubMed:17063000). {ECO:0000269\|PubMed:12724130, ECO:0000269\|PubMed:6752952}.
Tissue specificity:		In the inner ear, expressed in the lumen of the endolymphatic sac where it localizes to macrophage-like cells as well as to mitochondria-rich and ribosome-rich epithelial cells (at protein level) (PubMed:17063000). In the inner ear, expressed in marginal cells of the stria vascularis, epithelial cells at the spiral prominence, epithelial cells of Reissner's membrane facing the cochlear duct, and Kolliker's organ (at protein level) (PubMed:19202329). Expressed in the choroid plexus epithelium in the brain (at protein level) (PubMed:17324488). In the brain, also expressed in astrocytes (at protein level) (PubMed:18466341). Expression also detected in epithelial cells of the kidney glomerulus and proximal tubule, lung, epididymis and yolk sac (PubMed:7510321). {ECO:0000269\|PubMed:17063000, ECO:0000269\|PubMed:17324488, ECO:0000269\|PubMed:18466341, ECO:0000269\|PubMed:19202329, ECO:0000269\|PubMed:7510321}.
Developmental stage:		In the brain, expression is high after birth and gradually decreases from postnatal day 4 until the end of the first postnatal week. {ECO:0000269\|PubMed:18466341}.
Domain:		Two overlapping PxLPxI/L motifs mediate interaction with ankyrin repeats of ANKRA2. {ECO:0000269\|PubMed:22649097}.
Domain:		The cytoplasmic domain is required for sorting to the apical cell membrane. {ECO:0000269\|PubMed:12519751}.
Ptm:		A fraction undergoes proteolytic cleavage of the extracellular domain at the cell membrane to generate a cytoplasmic tail fragment. This is internalized into the early endosome from where it trafficks in an LDLRAP1/ARH-dependent manner to the endocytic recycling compartment (ERC). In the ERC, it is further cleaved by gamma-secretase to release a fragment which translocates to the nucleus and mediates transcriptional repression. {ECO:0000269\|PubMed:23836931}.
Ptm:		N-glycosylation is required for ligand binding. {ECO:0000250\|UniProtKB:A2ARV4}.
Similarity:		Belongs to the LDLR family. {ECO:0000305}.