Sortilin, SorCS1b, and SorLA Vps10p sorting receptors, are novel γ-secretase substrates
© Nyborg et al; licensee BioMed Central Ltd. 2006
Received: 26 April 2006
Accepted: 12 June 2006
Published: 12 June 2006
The mammalian Vps10p sorting receptor family is a group of 5 type I membrane homologs (Sortilin, SorLA, and SorCS1-3). These receptors bind various cargo proteins via their luminal Vps10p domains and have been shown to mediate a variety of intracellular sorting and trafficking functions. These proteins are highly expressed in the brain. SorLA has been shown to be down regulated in Alzheimer's disease brains, interact with ApoE, and modulate Aβ production. Sortilin has been shown to be part of proNGF mediated death signaling that results from a complex of Sortilin, p75NTR and proNGF. We have investigated and provide evidence for γ-secretase cleavage of this family of proteins.
We provide evidence that these receptors are substrates for presenilin dependent γ-secretase cleavage. γ-Secretase cleavage of these sorting receptors is inhibited by γ-secretase inhibitors and does not occur in PS1/PS2 knockout cells. Like most γ-secretase substrates, we find that ectodomain shedding precedes γ-secretase cleavage. The ectodomain cleavage is inhibited by a metalloprotease inhibitor and activated by PMA suggesting that it is mediated by an α-secretase like cleavage.
These data indicate that the α- and γ-secretase cleavages of the mammalian Vps10p sorting receptors occur in a fashion analogous to other known γ-secretase substrates, and could possibly regulate the biological functions of these proteins.
γ-Secretase is a multi-component protease complex comprised of Presenilin (PS) 1 or 2 with Aph-1, Pen-2, and Nicastrin [1, 2] that cleaves type I membrane proteins within their transmembrane domains. γ-Secretase catalyzes a number of important physiological and pathophysiological cleavages. Following ectodomain cleavage of the amyloid precursor protein (APP)  by β-secretase, γ-secretase cleavage releases the amyloid beta peptide (Aβ) that accumulates in the brains of patients with Alzheimer's disease (AD) . γ-Secretase also plays a key role in mediating signaling via the Notch receptors [5–7]. In most cases, knockout of presenilin or other components of the γ-secretase complex produces an embryonic lethal phenotype, that resembles the phenotype produced by knockout of Notch 1.
To date, more than 25 γ-secretase substrates have been identified. [8–28]. All identified γ-secretase substrates are type I transmembrane proteins  and contain a putative stop transfer sequence immediately following the transmembrane region . In most cases, ectodomain shedding precedes intramembrane γ-secretase cleavage . For a growing lists of substrates, γ-secretase cleavage has been shown to mediate downstream signaling events .
Following ectodomain shedding, γ-secretase cleavage liberates both the cytoplasmic fragment and a small secreted peptide. For several substrates the liberated cytoplasmic domain has been shown to translocate to the nucleus where it is involved in nuclear signaling (Notch ErbB4, Delta-1 Jagged, APLP1/2). This process is more generally referred to as regulated intramembrane proteolysis (RIP). RIP of Notch has been intensively studied. Ligand binding to the Notch extracellular domain results in ectodomain cleavage, which is then followed by γ-secretase cleavage. Once liberated the notch intracellular domain (NICD) translocates to the nucleus where it binds to CSL family of transcription factors [35, 36]. Notch binding to CSL has been shown to convert CSL from a transcriptional repressor to a transcriptional activator . Analogously nuclear signaling of the CD44 [37, 38] and N-cadherin  cytoplasmic domains following γ-secretase cleavage is indirectly achieved through CBP (CREB-binding protein) activation or suppression, respectively. In some cases nuclear translocation of the cytoplasmic domain is not required for signaling following γ-secretase cleavage [8, 13, 14, 40]. Not all γ-secretase substrates appear to undergo RIP, as ligand binding is not necessary for the initiation of cleavage. For example, APP does not appear to require ligand association in order to initiate ectodomain shedding which occurs prior to γ-secretase cleavage.
In most cases, signaling initiated by γ-secretase cleavage appears to be an activation event. However, cleavage of the substrate deleted in colorectal cancer (DCC) attenuates receptor-mediated intracellular signaling pathways that are critical in regulating glutamatergic synaptic transmission and memory processes [18, 41].
Because of their topologic similarity to other γ-secretase substrates and evidence for ectodomain shedding  (Figure 1a), we hypothesized that the mammalian Vps10p containing family of proteins might be γ-secretase substrates. Sortilin, SorLA and SorCS1, 2, and 3 comprise the five identified mammalian Vps10p sorting receptors and have a number of features in common. First, all are type I membrane proteins (Figure 1b). Second, all contain a luminal/extracellular cysteine-rich Vps10p domain homologous to the binding domain of the yeast sorting receptor for carboxypeptidase Y. Third, all contain a putative furin cleavage site. SorCS1-3 and SorLA also contain additional extracellular domains thought to be involved in ligand binding (Figure 1b). Sortilin is also known as neurotensin receptor 3 or gp95, and SorLA is often called LR11. These receptors are hypothesized to have pleiotropic functions in chaperoning and targeting various cargoes bound to their luminal Vps10p domains between various intracellular organelles [43, 44].
These sorting receptors are expressed at high levels in the CNS and in neurons [44–46]. Sortilin is part of the machinery that governs cell survival in developing neuronal tissue and a key determinant in the induction of posttraumatic neuronal apoptosis . It also mediates rapid endocytosis of lipoprotein lipase , neurotensin , and the proform of nerve growth factor . Sortilin has been shown to target proteins in the Golgi for transport to late endosomes. Of its many sorting and signaling functions, Sortilin was shown to play a role in p75NTR "death signaling". The cell death signal is a result of a complex of p75NTR, Sortilin and the precursor form of nerve growth factor (proNGF)  or pro brain-derived neurotrophic factor .
Recent data have suggested a role for SorLA in AD. SorLA was shown to be a receptor for, and interact with, ApoE [51–54]. In addition, it is reduced in AD brains versus age matched controls, interacts with APP  and regulates Aβ production [56, 57].
we provide evidence that Sortilin, SorCS1b and SorLA are sequentially cleaved by an α-secretase like activity followed by γ-secretase. α-Secretase cleavage results in secretion of a large extracellular domain of the Vps10p substrates and γ-secretase liberates a COOH-terminal fragment (CTF) from the membrane. These data extend very recent studies demonstrating that Sortilin, SorCS1, SorCS2, SorCS3, and SorLA undergo ectodomain shedding  and that SorLA can undergo γ-secretase cleavage .
Evidence for sequential α- and γ-secretase cleavage of Sortilin
The increase in 16 kDa sorV5 CTF resulting from γ-secretase inhibition suggested that the SorV5 CTF was a precursor to γ-secretase cleavage. We then expressed SorV5 in cells lacking PS1 and PS2. Transfection of SorV5 into PS-/- MEF cells resulted in an accumulation of the 16 kDa CTF (Figure 2b). Cotransfection of PS-/- MEF with SorV5 and either PS1 wt or a familial Alzheimer's disease linked mutant PS1 (M139V) caused the 16 kDa SorV5 CTF band to almost completely disappear (Figure 2b). Cotransfection of a dominant negative PS1 aspartate mutant (D385E) did not reduce levels of the 16 kDa SorV5 CTF. As expected, PS1 wt and M139V PS1 expression resulted in generation of endoproteolyzed PS1 CTF (Figure 2b); and expression of PS1 D385E resulted in accumulation of the PS1 holo protein (Figure 2b).
γ-secretase processing of SorV5 CTF in lipid rafts
Having observed the in vitro generation of a smaller SorV5 CTF in fractions 4 and 5 as a result of incubating at 37°C for 2 hours, we repeated the experiment with cells that had been pretreated with 50 μM IL-aldehyde, a γ-secretase inhibitor. These cells were lysed and sucrose gradient fractionated. Buoyant fractions 4 and 5 were combined and equal aliquots were incubated at 37°C for two hours plus and minus γ-secretase inhibitors. During the same period a negative control was incubated at 4°C for two hours. As shown in Figure 3a, when the buoyant fractions were incubated at 37°C for two hours a smaller SorV5 CTF band was generated (figure 3b DMSO). In the sample that remained at 4°C during the incubation period or those incubated in the presence of γ-secretase inhibitors no smaller SorV5 CTF was detected (Figure 3b). Furthermore, generation of the smaller SorV5 CTF was inhibited by another γ-secretase inhibitor (LY411,575) in a dose dependant fashion (Figure 3c). Anti-PS1NT antibody was used to demonstrate loading consistency.
SorCS1b, evidence for α and γ-secretase processing of a second mammalian Vps10p
PS dependant SorLA processing
To date, more than 25 γ-secretase substrates have been identified (Figure 1a). γ-Secretase cleavage of certain substrates mediates normal physiologic signaling. Given the growing list of substrates, it has been postulated that γ-secretase may function much like the proteosome of the membrane assisting in the degradation of type I transmembrane proteins by liberating them from the membrane . This notion may be supported by the promiscuity with which γ-secretase cleaves multiple substrates at a variety of different sites (Figure 1a). It is possible that overexpression of type I transmembrane proteins may result in non-physiologic γ-secretase cleavage. However, to date, all γ-secretase substrates initially identified using overexpression studies in eukaryotic cells have proven to be authentic endogenous substrates. Indeed, numerous γ-secretase substrates like APP, Notch, and CD44 have withstood the scrutiny of genetic, biochemical, animal model data that establish both their authenticity as true γ-secretase substrates and the physiologic relevance of γ-secretase cleavage.
Sortilin, SorCS1b and SorLA are all members of the mammalian Vps10p sorting receptor family. In this manuscript we provide several lines of evidence that these proteins are γ-secretase substrates. We detect truncated CTF derived from COOH-terminally V5 epitope tagged Sortilin and SorCS1b and untagged SorLA. These CTF appear to be derived from the holoproteins by an α-secretase like activity. γ-Secretase inhibitors and expression of the proteins in presenilin knockout cells results in marked accumulation of these CTF, a phenomena reversed by expression wt or FAD-linked mutant PS1. These CTF are enriched in buoyant lipid raft fractions where γ-secretase activity resides. Incubation of SorV5 or SorCS1bV5 CTF containing raft fractions leads to generation of a smaller cleavage product in the case of Sortilin and a decrease of the CTF in the case of SorCS1bV5. The generation of the smaller SorV5 CTF and the decrease in SorCS1bV5 CTF are inhibited by a γ-secretase inhibitor. Collectively these data indicate that γ-secretase has the capacity to cleave overexpressed Sortilin, SorCS1b and SorLA.
During the preparation of this manuscript evidence was reported that SorLA was a γ-secretase substrate . Bohm et al demonstrated that Myc tagged SorLA underwent PS dependent γ-secretase processing and that following γ-secretase cleavage the cytoplasmic portion was found in the nucleus . Combined with our data, demonstrating that Sortilin, SorCS1b, and SorLa are γ-secretase substrates, these data provide evidence that the entire family of mammalian Vps10p containing type I proteins may contain important biologically active signaling peptides in their COOH-termini.
Studies showing intramembrane γ-secretase cleavage of endogenous Vps10p sorting receptor will be needed to show that these proteins are in fact authentic γ-secretase substrates. As noted before it is unlikely that the overexpression studies performed here will be misleading. Given the complex trafficking, sorting, and signaling functions mediated by mammalian Vps10p sorting receptors it will be interesting to determine whether γ-secretase cleavage regulates the normal function of these proteins. Indeed, it may be that some of the trafficking deficits in PS deficient cells could be attributed to the lack of γ-secretase cleavage of several Vps10p proteins. Though speculative there is some evidence that Vps10p receptors may play a role in AD and in neuronal death. SorLA has been shown to be down regulated in AD, and plays a role in APP trafficking and Aβ production [56, 71]. Neuronal death signaling was shown to result from a complex of two γ-substrates, Sortilin and p75NTR [13, 14], in conjunction with proNGF or proBDNF . Additional studies are needed to clarify the physiologic and possible pathologic role of γ-secretase cleavage of mammalian Vps10p sorting receptors.
Materials and methods
Full length Sortilin and SorCS1b plasmid constructs were purchased from Origene. A V5 epitope was cloned into the pCMV6-XL plasmid at the COOH-terminus immediately preceding the stop codon (SorV5 and SorCS1V5). SorLA wt plasmid was described previously . PS1 wt, M139V, and D385E were described previously . All constructs were verified by sequencing.
DNA transfection of PS-/-MEF cells
Mouse embryonic fibroblasts (MEF) deficient in both PS1 and PS2 (PS-/-) were characterized previously . Efficient transfection of these cells was achieved using the Amaxa nucleofector system. Briefly, using the Amaxa MEF kit 2, 3 μg of DNA and 3 × 10^6 cells/reaction the transfection was performed with the "O-05" mouse neuron program. Transfected cells were plated on 10 cm plate with 8 ml of growth media. Cells were harvested after 24 hours.
SorV5 and SorCS1bV5 stable cell lines and culture
Human embryonic kidney (HEK) 293 cells were transfected in reduced serum Opti-Mem (Gibco) with 2 μg of DNA and 8 μl of Fugene. Cells were incubated for 6 hours and then allowed to equilibrate in standard growth media (DMEM 2% fetal bovine serum, 8% normal calf serum, 1% penicillin streptomycin) for 24 hours. Selection antibiotic was then added to the cells and maintained throughout the experiments. Transient expression experiments were performed the same but with HEK 293T cells.
Cells treated with inhibitors were incubated for 18 hours using the concentration reported and 1% DMSO. phorbol 12-myristate-13-acetate (PMA) treatment was performed for 4 hours.
Inhibitors were all generated by the Mayo Clinic Chemistry core using published methods for each. All compounds were verified by NMR and Mass Spectroscopy.
Lysis, antibodies, and Western blotting
Cells were lysed in 1% triton × 100 with 1× complete protease inhibitor (Roche) unless otherwise stated. Cell lysates were then spun at 14,000 RPM for 2 minutes to remove nuclei. BioRad XT loading buffer with reducing solution was added to each sample. SDS-PAGE was performed using BioRad Criterion gel system. 12% Bis-Tris XT gels were used unless otherwise stated with BioRad MES buffer. Gels were transferred to Millipore low-fluor PVDF for 90 minutes and 160 volts. Membranes were blocked in caesine (0.25%) and phosphate buffered saline solution and primary antibodies were used at the reported concentration in the blocking solution overnight at 4°C. Anti-V5 (Invitrogen) and anti-β-actin antibody (Sigma) antibodies were used at 1:1000. The anti-PS1 NTF (A4 from Dr. Paul Fraser) antibody I think) and anti-PS1 CTF (490) were used at 1:1000. The anti-SorLAct antibody was used at 1:500 . Fluorescent antibodies containing either the 680 or 800 fluorophore were incubated with the membrane for 1 hour at room temperature at 1:20,000. Fluorescently labeled protein detection was performed using the Odyssey Scanner.
Sucrose gradients were run as described previously . Briefly, cells were washed with 5 mL of ice cold PBS (pH 7.4) and lysed in 2.5 mL of 2% CHAPSO 0.15 M Na Citrate (pH 7.0) with 1× protease inhibitor cocktail (complete PI, Roche). The cleared lysate was then sequentially diluted with sucrose containing 0.15 M Na Citrate (pH 7.0) so that the final concentration of CHAPSO was 0.25% and sucrose was 45%. Four ml of this homogenate was then applied to the bottom of the centrifuge tube, and sequentially overlaid with 4 ml of 0.15 M Na Citrate (pH 7.0), 35% sucrose, 0.25% CHAPSO followed by 4 ml of 0.15 M Na Citrate (pH 7.0), 5% sucrose, 0.25% CHAPSO. The gradient was centrifuged for 19 hrs at 39,000 rpm in an SW-41 Ti rotor (Beckman) at 4°C. Following centrifugation, 1 mL fractions were collected from the top of the gradient.
CTF, COOH-terminal fragment
sortilin that contain a COOH-terminal V5 his epitope tag
SorCs1b that contain a COOH-terminal V5 his epitope tag
amyloid precursor protein
regulated intramembrane proteolysis
Notch intracellular domain
CREBP binding protein
deleted in colorectal cancer protein
antibody specific to the COOH-terminus of SorLA
mouse embryonic fibroblasts
proform of nerve growth factor
soluble NH2-terminal fragment of Sortilin
human embryonic kidney cell line
MEF cells that PS1 and PS2 are knocked out
We thank members of the Golde Lab for their critical analyses and thoughtful contributions. This work was supported by the Mayo Foundation and an NIH/NINDS grant NS39072 to T.E.G.
- Marlow L, Canet RM, Haugabook SJ, Hardy JA, Lahiri DK, Sambamurti K: APH1, PEN2, and Nicastrin increase Abeta levels and gamma-secretase activity. Biochem Biophys Res Commun. 2003, 305: 502-509. 10.1016/S0006-291X(03)00797-6.View ArticlePubMedGoogle Scholar
- Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C: Reconstitution of gamma-secretase activity. Nat Cell Biol. 2003, 5: 486-488. 10.1038/ncb960.View ArticlePubMedGoogle Scholar
- Wolfe MS, Xia WM, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ: Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999, 398: 513-517. 10.1038/19077.View ArticlePubMedGoogle Scholar
- Kang J, Lemaire H-G, Unterbeck A, Salbaum JM, Masters CL, Grzeschik K-H, Multhaup G, Beyreuther K, Muller-Hill B: The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987, 325: 733-736. 10.1038/325733a0.View ArticlePubMedGoogle Scholar
- Schroeter EH, Kisslinger JA, Kopan R: Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain [see comments]. Nature. 1998, 393: 382-386. 10.1038/30756.View ArticlePubMedGoogle Scholar
- De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, et al: A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999, 398: 518-522. 10.1038/19083.View ArticlePubMedGoogle Scholar
- Struhl G, Greenwald I: Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature. 1999, 398: 522-525. 10.1038/19091.View ArticlePubMedGoogle Scholar
- Marambaud P, Shioi J, Serban G, Georgakopoulos A, Sarner S, Nagy V, Baki L, Wen P, Efthimiopoulos S, Shao Z, et al: A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. Embo J. 2002, 21: 1948-1956. 10.1093/emboj/21.8.1948.PubMed CentralView ArticlePubMedGoogle Scholar
- Kim DY, MacKenzie Ingano LA, Kovacs DM: Nectin-1a, an immunoglobulin-like receptor involved in the formation of synapses, is a substrate for presenilin/g-secretase-like cleavage. J Biol Chem. 2002, 9: 9-Google Scholar
- Lammich S, Okochi M, Takeda M, Kaether C, Capell A, Zimmer AK, Edbauer D, Walter J, Steiner H, Haass C: Presenilin-dependent Intramembrane Proteolysis of CD44 Leads to the Liberation of Its Intracellular Domain and the Secretion of an Abeta – like Peptide. J Biol Chem. 2002, 277: 44754-44759. 10.1074/jbc.M206872200.View ArticlePubMedGoogle Scholar
- Andersson CX, Fernandez-Rodriguez J, Laos S, Baeckstrom D, Haass C, Hansson GC: Shedding and gamma-secretase-mediated intramembrane proteolysis of the mucin-type molecule CD43. Biochem J. 2005, 387: 377-384. 10.1042/BJ20041387.PubMed CentralView ArticlePubMedGoogle Scholar
- Ni CY, Murphy MP, Golde TE, Carpenter G: gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science. 2001, 294: 2179-2181. 10.1126/science.1065412.View ArticlePubMedGoogle Scholar
- Kanning KC, Hudson M, Amieux PS, Wiley JC, Bothwell M, Schecterson LC: Proteolytic processing of the p75 neurotrophin receptor and two homologs generates C-terminal fragments with signaling capability. J Neurosci. 2003, 23: 5425-5436.PubMedGoogle Scholar
- Jung KM, Tan S, Landman N, Petrova K, Murray S, Lewis R, Kim PK, Kim DS, Ryu SH, Chao MV, Kim TW: Regulated intramembrane proteolysis of the p75 neurotrophin receptor modulates its association with the TrkA receptor. J Biol Chem. 2003, 278: 42161-42169. 10.1074/jbc.M306028200.View ArticlePubMedGoogle Scholar
- May P, Reddy YK, Herz J: Proteolytic processing of low density lipoprotein receptor-related protein mediates regulated release of its intracellular domain. J Biol Chem. 2002, 277: 18736-18743. 10.1074/jbc.M201979200.View ArticlePubMedGoogle Scholar
- Hoe HS, Rebeck GW: Regulation of ApoE receptor proteolysis by ligand binding. Brain Res Mol Brain Res. 2005, 137: 31-39. 10.1016/j.molbrainres.2005.02.013.View ArticlePubMedGoogle Scholar
- Schulz JG, Annaert W, Vandekerckhove J, Zimmermann P, De Strooper B, David G: Syndecan 3 intramembrane proteolysis is presenilin/gamma-secretase-dependent and modulates cytosolic signaling. J Biol Chem. 2003, 278: 48651-48657. 10.1074/jbc.M308424200.View ArticlePubMedGoogle Scholar
- Taniguchi Y, Kim SH, Sisodia SS: Presenilin-dependent "gamma-secretase" processing of deleted in colorectal cancer (DCC). J Biol Chem. 2003, 278: 30425-30428. 10.1074/jbc.C300239200.View ArticlePubMedGoogle Scholar
- Scheinfeld MH, Ghersi E, Laky K, Fowlkes BJ, D'Adamio L: Processing of beta-amyloid precursor-like protein-1 and -2 by gamma-secretase regulates transcription. J Biol Chem. 2002, 277: 44195-44201. 10.1074/jbc.M208110200.View ArticlePubMedGoogle Scholar
- Ikeuchi T, Sisodia SS: The Notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent "gamma-secretase" cleavage. J Biol Chem. 2003, 278: 7751-7754. 10.1074/jbc.C200711200.View ArticlePubMedGoogle Scholar
- LaVoie MJ, Selkoe DJ: The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments. J Biol Chem. 2003, 278: 34427-34437. 10.1074/jbc.M302659200.View ArticlePubMedGoogle Scholar
- Cowan JW, Wang X, Guan R, He K, Jiang J, Baumann G, Black RA, Wolfe MS, Frank SJ: Growth hormone receptor is a target for presenilin-dependent gamma-secretase cleavage. J Biol Chem. 2005, 280: 19331-19342. 10.1074/jbc.M500621200.View ArticlePubMedGoogle Scholar
- Wong HK, Sakurai T, Oyama F, Kaneko K, Wada K, Miyazaki H, Kurosawa M, De Strooper B, Saftig P, Nukina N: beta Subunits of voltage-gated sodium channels are novel substrates of beta-site amyloid precursor protein-cleaving enzyme (BACE1) and gamma-secretase. J Biol Chem. 2005, 280: 23009-23017. 10.1074/jbc.M414648200.View ArticlePubMedGoogle Scholar
- Gowrishankar K, Zeidler MG, Vincenz C: Release of a membrane-bound death domain by gamma-secretase processing of the p75NTR homolog NRADD. J Cell Sci. 2004, 117: 4099-4111. 10.1242/jcs.01263.View ArticlePubMedGoogle Scholar
- Araki Y, Miyagi N, Kato N, Yoshida T, Wada S, Nishimura M, Komano H, Yamamoto T, De Strooper B, Yamamoto K, Suzuki T: Coordinated metabolism of Alcadein and amyloid beta-protein precursor regulates FE65-dependent gene transactivation. J Biol Chem. 2004, 279: 24343-24354. 10.1074/jbc.M401925200.View ArticlePubMedGoogle Scholar
- Cai J, Jiang WG, Grant MB, Boulton M: Pigment epithelium-derived factor inhibits angiogenesis via regulated intracellular proteolysis of vascular endothelial growth factor receptor 1. J Biol Chem. 2006, 281: 3604-3613. 10.1074/jbc.M507401200.View ArticlePubMedGoogle Scholar
- Biemesderfer D: Regulated intramembrane proteolysis of megalin: Linking urinary protein and gene regulation in proximal tubule?. Kidney Int. 2006Google Scholar
- Bohm C, Seibel N, Henkel B, Steiner H, Haass C, Hampe W: SorLA signaling by regulated intramembrane proteolysis. J Biol Chem. 2006Google Scholar
- Golde TE, Eckman CB: Physiologic and pathologic events mediated by intramembranous and juxtamembranous proteolysis. Sci STKE. 2003, 2003: RE4-PubMedGoogle Scholar
- Yost CS, Hedgpeth J, Lingappa VR: A stop transfer sequence confers predictable transmembrane orientation to a previously secreted protein in cell-free systems. Cell. 1983, 34: 759-766. 10.1016/0092-8674(83)90532-9.View ArticlePubMedGoogle Scholar
- Xia W, Wolfe MS: Intramembrane proteolysis by presenilin and presenilin-like proteases. J Cell Sci. 2003, 116: 2839-2844. 10.1242/jcs.00651.View ArticlePubMedGoogle Scholar
- Landman N, Kim TW: Got RIP? Presenilin-dependent intramembrane proteolysis in growth factor receptor signaling. Cytokine Growth Factor Rev. 2004, 15: 337-351. 10.1016/j.cytogfr.2004.04.001.View ArticlePubMedGoogle Scholar
- Pollack SJ, Lewis H: Secretase inhibitors for Alzheimer's disease: challenges of a promiscuous protease. Curr Opin Investig Drugs. 2005, 6: 35-47.PubMedGoogle Scholar
- Murphy MP, Uljon SN, Golde TE, Wang R: FAD-linked mutations in presenilin 1 alter the length of Abeta peptides derived from betaAPP transmembrane domain mutants. Biochim Biophys Acta. 2002, 1586: 199-209.View ArticlePubMedGoogle Scholar
- Louvi A, Artavanis-Tsakonas S: Notch signalling in vertebrate neural development. Nat Rev Neurosci. 2006, 7: 93-102. 10.1038/nrn1847.View ArticlePubMedGoogle Scholar
- Fortini ME: Notch and presenilin: a proteolytic mechanism emerges. Curr Opin Cell Biol. 2001, 13: 627-634. 10.1016/S0955-0674(00)00261-1.View ArticlePubMedGoogle Scholar
- Murakami D, Okamoto I, Nagano O, Kawano Y, Tomita T, Iwatsubo T, De Strooper B, Yumoto E, Saya H: Presenilin-dependent gamma-secretase activity mediates the intramembranous cleavage of CD44. Oncogene. 2003, 22: 1511-1516. 10.1038/sj.onc.1206298.View ArticlePubMedGoogle Scholar
- Okamoto I, Kawano Y, Murakami D, Sasayama T, Araki N, Miki T, Wong AJ, Saya H: Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway. J Cell Biol. 2001, 155: 755-762. 10.1083/jcb.200108159.PubMed CentralView ArticlePubMedGoogle Scholar
- Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, Robakis NK: A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell. 2003, 114: 635-645. 10.1016/j.cell.2003.08.008.View ArticlePubMedGoogle Scholar
- Georgakopoulos A, Marambaud P, Efthimiopoulos S, Shioi J, Cui W, Li HC, Schutte M, Gordon R, Holstein GR, Martinelli G, et al: Presenilin-1 forms complexes with the cadherin/catenin cell-cell adhesion system and is recruited to intercellular and synaptic contacts. Mol Cell. 1999, 4: 893-902. 10.1016/S1097-2765(00)80219-1.View ArticlePubMedGoogle Scholar
- Parent AT, Barnes NY, Taniguchi Y, Thinakaran G, Sisodia SS: Presenilin attenuates receptor-mediated signaling and synaptic function. J Neurosci. 2005, 25: 1540-1549. 10.1523/JNEUROSCI.3850-04.2005.View ArticlePubMedGoogle Scholar
- Hermey G, Sjogaard S, Petersen CM, Nykjaer A, Gliemann J: Tumour necrosis factor-alpha convertase mediates ectodomain shedding of Vps10p-domain receptor family members. Biochem J. 2006Google Scholar
- Petersen CM, Nielsen MS, Nykjaer A, Jacobsen L, Tommerup N, Rasmussen HH, Roigaard H, Gliemann J, Madsen P, Moestrup SK: Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography. J Biol Chem. 1997, 272: 3599-3605. 10.1074/jbc.272.6.3599.View ArticlePubMedGoogle Scholar
- Mazella J: Sortilin/neurotensin receptor-3: a new tool to investigate neurotensin signaling and cellular trafficking?. Cell Signal. 2001, 13: 1-6. 10.1016/S0898-6568(00)00130-3.View ArticlePubMedGoogle Scholar
- Hermey G, Riedel IB, Hampe W, Schaller HC, Hermans-Borgmeyer I: Identification and characterization of SorCS, a third member of a novel receptor family. Biochem Biophys Res Commun. 1999, 266: 347-351. 10.1006/bbrc.1999.1822.View ArticlePubMedGoogle Scholar
- Gutekunst CA, Torre ER, Sheng Z, Yi H, Coleman SH, Riedel IB, Bujo H: Stigmoid bodies contain type I receptor proteins SorLA/LR11 and sortilin: new perspectives on their function. J Histochem Cytochem. 2003, 51: 841-852.View ArticlePubMedGoogle Scholar
- Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, Jacobsen C, Kliemannel M, Schwarz E, Willnow TE, et al: Sortilin is essential for proNGF-induced neuronal cell death. Nature. 2004, 427: 843-848. 10.1038/nature02319.View ArticlePubMedGoogle Scholar
- Nielsen MS, Jacobsen C, Olivecrona G, Gliemann J, Petersen CM: Sortilin/neurotensin receptor-3 binds and mediates degradation of lipoprotein lipase. J Biol Chem. 1999, 274: 8832-8836. 10.1074/jbc.274.13.8832.View ArticlePubMedGoogle Scholar
- Morinville A, Martin S, Lavallee M, Vincent JP, Beaudet A, Mazella J: Internalization and trafficking of neurotensin via NTS3 receptors in HT29 cells. Int J Biochem Cell Biol. 2004, 36: 2153-2168. 10.1016/j.biocel.2004.04.013.View ArticlePubMedGoogle Scholar
- Teng HK, Teng KK, Lee R, Wright S, Tevar S, Almeida RD, Kermani P, Torkin R, Chen ZY, Lee FS, et al: ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci. 2005, 25: 5455-5463. 10.1523/JNEUROSCI.5123-04.2005.View ArticlePubMedGoogle Scholar
- Yamazaki H, Bujo H, Kusunoki J, Seimiya K, Kanaki T, Morisaki N, Schneider WJ, Saito Y: Elements of neural adhesion molecules and a yeast vacuolar protein sorting receptor are present in a novel mammalian low density lipoprotein receptor family member. J Biol Chem. 1996, 271: 24761-24768. 10.1074/jbc.271.11.6483.View ArticlePubMedGoogle Scholar
- Taira K, Bujo H, Hirayama S, Yamazaki H, Kanaki T, Takahashi K, Ishii I, Miida T, Schneider WJ, Saito Y: LR11, a mosaic LDL receptor family member, mediates the uptake of ApoE-rich lipoproteins in vitro. Arterioscler Thromb Vasc Biol. 2001, 21: 1501-1506.View ArticlePubMedGoogle Scholar
- Zhu Y, Bujo H, Yamazaki H, Hirayama S, Kanaki T, Takahashi K, Shibasaki M, Schneider WJ, Saito Y: Enhanced expression of the LDL receptor family member LR11 increases migration of smooth muscle cells in vitro. Circulation. 2002, 105: 1830-1836. 10.1161/01.CIR.0000014413.91312.EF.View ArticlePubMedGoogle Scholar
- Zhu Y, Bujo H, Yamazaki H, Ohwaki K, Jiang M, Hirayama S, Kanaki T, Shibasaki M, Takahashi K, Schneider WJ, Saito Y: LR11, an LDL receptor gene family member, is a novel regulator of smooth muscle cell migration. Circ Res. 2004, 94: 752-758. 10.1161/01.RES.0000120862.79154.0F.View ArticlePubMedGoogle Scholar
- Andersen OM, Schmidt V, Spoelgen R, Gliemann J, Behlke J, Galatis D, McKinstry WJ, Parker MW, Masters CL, Hyman BT, et al: Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11. Biochemistry. 2006, 45: 2618-2628. 10.1021/bi052120v.View ArticlePubMedGoogle Scholar
- Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T, Jansen P, Wu X, et al: Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci USA. 2005, 102: 13461-13466. 10.1073/pnas.0503689102.PubMed CentralView ArticlePubMedGoogle Scholar
- Offe K, Dodson SE, Shoemaker JT, Fritz JJ, Gearing M, Levey AI, Lah JJ: The lipoprotein receptor LR11 regulates amyloid beta production and amyloid precursor protein traffic in endosomal compartments. J Neurosci. 2006, 26: 1596-1603. 10.1523/JNEUROSCI.4946-05.2006.PubMed CentralView ArticlePubMedGoogle Scholar
- Mazella J, Zsurger N, Navarro V, Chabry J, Kaghad M, Caput D, Ferrara P, Vita N, Gully D, Maffrand JP, Vincent JP: The 100-kDa neurotensin receptor is gp95/sortilin, a non-G-protein-coupled receptor. J Biol Chem. 1998, 273: 26273-26276. 10.1074/jbc.273.41.26273.View ArticlePubMedGoogle Scholar
- Buxbaum J, Oishi M, Chen H, Pinkas-Kramarski R, Jaffe E, Gandy S, Greengard P: Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer ß/A4 precursor. Proc Natl Acad Sci USA. 1992, 89: 10075-10078. 10.1073/pnas.89.21.10075.PubMed CentralView ArticlePubMedGoogle Scholar
- Caporaso GL, Gandy SE, Buxbaum JD, Ramabhadran TV: Protein phosphorylation regulates secretion of Alzheimer ß/A4 amyloid precursor protein. Proc Natl Acad Sci USA. 1992, 89: 3055-3059. 10.1073/pnas.89.7.3055.PubMed CentralView ArticlePubMedGoogle Scholar
- Nitsch RM, Slack BE, Wurtman RJ, Growdon JH: Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science. 1992, 258: 304-307.View ArticlePubMedGoogle Scholar
- Wolf BA, Wertkin AM, Jolly YC, Yasuda RP, Wolfe BB, Konrad RJ, Manning D, Ravi S, Williamson JR, Lee VM-Y: Muscarinic regulation of Alzheimer's disease amyloid precursor protein (APP) secretion and amyloid ß-protein (Aß) production in human neuronal NT2N cells. J Biol Chem. 1995, 270: 4916-4922. 10.1074/jbc.270.9.4916.View ArticlePubMedGoogle Scholar
- Endres K, Postina R, Schroeder A, Mueller U, Fahrenholz F: Shedding of the amyloid precursor protein-like protein APLP2 by disintegrin-metalloproteinases. Febs J. 2005, 272: 5808-5820. 10.1111/j.1742-4658.2005.04976.x.View ArticlePubMedGoogle Scholar
- Wahrle S, Das P, Nyborg AC, McLendon C, Shoji M, Kawarabayashi T, Younkin LH, Younkin SG, Golde TE: Cholesterol-Dependent gamma-Secretase Activity in Buoyant Cholesterol- Rich Membrane Microdomains. Neurobiol Dis. 2002, 9: 11-23. 10.1006/nbdi.2001.0470.View ArticlePubMedGoogle Scholar
- Wada S, Morishima-Kawashima M, Qi Y, Misono H, Shimada Y, Ohno-Iwashita Y, Ihara Y: Gamma-secretase activity is present in rafts but is not cholesterol-dependent. Biochemistry. 2003, 42: 13977-13986. 10.1021/bi034904j.View ArticlePubMedGoogle Scholar
- Vetrivel KS, Cheng H, Lin W, Sakurai T, Li T, Nukina N, Wong PC, Xu H, Thinakaran G: Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes. J Biol Chem. 2004, 279: 44945-44954. 10.1074/jbc.M407986200.PubMed CentralView ArticlePubMedGoogle Scholar
- Urano Y, Hayashi I, Isoo N, Reid PC, Shibasaki Y, Noguchi N, Tomita T, Iwatsubo T, Hamakubo T, Kodama T: Association of active gamma-secretase complex with lipid rafts. J Lipid Res. 2005, 46: 904-912. 10.1194/jlr.M400333-JLR200.View ArticlePubMedGoogle Scholar
- Hermey G, Keat SJ, Madsen P, Jacobsen C, Petersen CM, Gliemann J: Characterization of sorCS1, an alternatively spliced receptor with completely different cytoplasmic domains that mediate different trafficking in cells. J Biol Chem. 2003, 278: 7390-7396. 10.1074/jbc.M210851200.View ArticlePubMedGoogle Scholar
- Lintzel J, Franke I, Riedel IB, Schaller HC, Hampe W: Characterization of the VPS10 domain of SorLA/LR11 as binding site for the neuropeptide HA. Biol Chem. 2002, 383: 1727-1733. 10.1515/BC.2002.193.View ArticlePubMedGoogle Scholar
- Kopan R, Ilagan MX: Gamma-secretase: proteasome of the membrane?. Nat Rev Mol Cell Biol. 2004, 5: 499-504. 10.1038/nrm1406.View ArticlePubMedGoogle Scholar
- Scherzer CR, Offe K, Gearing M, Rees HD, Fang G, Heilman CJ, Schaller C, Bujo H, Levey AI, Lah JJ: Loss of apolipoprotein E receptor LR11 in Alzheimer disease. Arch Neurol. 2004, 61: 1200-1205. 10.1001/archneur.61.8.1200.View ArticlePubMedGoogle Scholar
- Herreman A, Serneels L, Annaert W, Collen D, Schoonjans L, De Strooper B: Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells. Nat Cell Biol. 2000, 2: 461-462. 10.1038/35017105.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.