Surface expression and limited proteolysis of ADAM10 are increased by a dominant negative inhibitor of dynamin
© Carey et al; licensee BioMed Central Ltd. 2011
Received: 26 August 2010
Accepted: 17 May 2011
Published: 17 May 2011
The amyloid precursor protein (APP) is cleaved by β- and γ-secretases to generate toxic amyloid β (Aβ) peptides. Alternatively, α-secretases cleave APP within the Aβ domain, precluding Aβ formation and releasing the soluble ectodomain, sAPPα. We previously showed that inhibition of the GTPase dynamin reduced APP internalization and increased release of sAPPα, apparently by prolonging the interaction between APP and α-secretases at the plasma membrane. This was accompanied by a reduction in Aβ generation. In the present study, we investigated whether surface expression of the α-secretase ADAM (a d isintegrin a nd m etalloprotease)10 is also regulated by dynamin-dependent endocytosis.
Transfection of human embryonic kidney (HEK) cells stably expressing M3 muscarinic receptors with a dominant negative dynamin I mutant (dyn I K44A), increased surface expression of both immature, and mature, catalytically active forms of co-expressed ADAM10. Surface levels of ADAM10 were unaffected by activation of protein kinase C (PKC) or M3 receptors, indicating that receptor-coupled shedding of the ADAM substrate APP is unlikely to be mediated by inhibition of ADAM10 endocytosis in this cell line. Dyn I K44A strongly increased the formation of a C-terminal fragment of ADAM10, consistent with earlier reports that the ADAM10 ectodomain is itself a target for sheddases. The abundance of this fragment was increased in the presence of a γ-secretase inhibitor, but was not affected by M3 receptor activation. The dynamin mutant did not affect the distribution of ADAM10 and its C-terminal fragment between raft and non-raft membrane compartments.
Surface expression and limited proteolysis of ADAM10 are regulated by dynamin-dependent endocytosis, but are unaffected by activation of signaling pathways that upregulate shedding of ADAM substrates such as APP. Modulation of ADAM10 internalization could affect cellular behavior in two ways: by altering the putative signaling activity of the ADAM10 C-terminal fragment, and by regulating the biological function of ADAM10 substrates such as APP and N-cadherin.
Keywordsa d isintegrin a nd m etalloprotease (ADAM)10 dynamin, amyloid precursor protein (APP) muscarinic receptor protein kinase C (PKC) endocytosis
The pathogenesis of Alzheimer's disease (AD) is due, at least in part, to the formation in brain of insoluble protein deposits known as amyloid plaques. The principal component of the plaques, a neurotoxic, self-aggregating peptide known as amyloid β (Aβ), is generated by successive cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Alternatively, APP may be cleaved within its Aβ domain by α-secretases, precluding the formation of Aβ, and releasing sAPPα, a large soluble N-terminal fragment, from the cell surface. An alteration in the balance between these alternative proteolytic pathways may underlie the pathogenic process in AD [1–3]. Recent research has identified the ADAM (a d isintegrin a nd m etalloprotease) family of zinc metalloproteases, particularly ADAM10 and ADAM17/TACE (tumor necrosis factor α convertase), as α-secretases [4, 5]. ADAMs cleave a variety of transmembrane proteins, including APP, within their extracellular domains, resulting in shedding of the ectodomain fragment . Multiple receptor ligands, as well as direct activators of protein kinase C (PKC), stimulate ectodomain shedding of APP and other proteins . However, phosphorylation of the cytoplasmic domain of APP does not appear to be necessary for signal-regulated shedding of APP [7, 8]. Neither does truncation of the cytoplasmic domain of ADAM17 prevent upregulation of its activity toward several of its substrates, including tumor necrosis factor α, by phorbol ester [9, 10]. On the other hand, signal-activated shedding of TrkA and the prion protein was reported to be at least partially dependent on phosphorylation of threonine 735 within the cytoplasmic domain of ADAM17/TACE by mitogen-activated protein kinase [11, 12]. Taken together, the evidence suggests that multiple mechanisms contribute to signal-mediated upregulation of ectodomain shedding by ADAMs.
Mutation of internalization motifs within the C-terminus of APP, or removal of the C-terminal tail, increases surface expression of APP, and release of sAPPα [13, 14]. Blocking the function of the endocytic protein dynamin by transfecting cells with dyn I K44A, a dominant-negative dynamin I mutant , exerts similar effects [16, 17] suggesting that inhibition of endocytosis promotes ectodomain shedding by prolonging the interaction between APP and α-secretases on the plasma membrane. Because PKC phosphorylates dynamin, preventing it from associating with membrane phospholipids , we hypothesized that inhibition of dynamin function might be the mechanism underlying kinase-dependent sAPPα release. However, the PKC activator phorbol 12-myristate 13-acetate (PMA) did not affect the rate of APP internalization in HEK cells stably transfected with APP695.
It was recently reported that ADAM10 is cleaved within its ectodomain by ADAM9 or ADAM15, generating a C-terminal fragment (CTF) that is then proteolyzed by γ-secretase [19–21]. The released intracellular domain subsequently translocates to the nucleus . Thus, like APP, ADAM10 undergoes sequential two-step proteolysis to generate a fragment with potential signaling capabilities. Our results show that inhibition of dynamin-dependent endocytosis increases surface expression of mature ADAM10, and potentiates the formation of the ADAM10 CTF. Activation of PKC, or M3 muscarinic receptors, did not affect ADAM10 surface expression or CTF formation, suggesting that receptor- or PKC-mediated stimulation of APP shedding in these cells is not dependent on alterations in ADAM10 trafficking or proteolysis. Other physiological mechanisms that could regulate ADAM10 internalization, such as interactions with other cell surface proteins, have the potential to alter generation of the CTF, thereby modulating its putative signaling actions.
Inhibition of dynamin function increases surface expression of ADAM10
ADAM10 overexpression increases constitutive, but not M3 receptor-evoked release of sAPPα
Proteolytic processing of ADAM10 is increased by dynamin inhibition, but is unaffected by carbachol
Dynamin inhibition does not alter the distribution of ADAM10 in raft and non-raft compartments
Dynamin regulates N-cadherin proteolysis
These results, and earlier work from our laboratory and others, indicate that dynamin regulates internalization and proteolytic processing of both ADAM10 and its substrate APP [16, 17]. To extend this investigation to other transmembrane proteins, we examined the effect of the dynamin mutant on proteolytic processing of N-cadherin, an adhesion protein that is a substrate for ADAM10 and γ-secretase [35, 36]. HEK-M3 cells were transiently transfected with human N-cadherin and either empty vector, or dyn I K44A, separated into detergent-soluble and insoluble fractions, and subjected to immunoblot analysis. The abundance of a ~40 kDa CTF of N-cadherin, a fragment previously shown to be a product of ADAM-mediated proteolysis [35, 36], was increased in cells co-expressing dyn I K44A. The increase was more prominent in the non-raft compartment (Figure 6C). These results suggest that, as shown for APP and ADAM10, inhibition of dynamin function increases ADAM-mediated cleavage of N-cadherin, thereby promoting formation of a CTF. In the case of N-cadherin, increasing its proteolysis may potentiate its ability to act as a repressor of the transcriptional coactivator CBP (CREB binding protein) .
Cleavage of APP by the α-secretases, ADAM10 and ADAM17/TACE, is of physiological importance because it precludes the formation of the toxic Aβ peptide. Moreover, the secreted APP ectodomain fragment, sAPPα, promotes neural plasticity and neurogenesis, and exhibits neuroprotective properties . G-protein coupled receptors, and compounds such as phorbol esters that directly activate PKC, increase cleavage of sAPPα by α-secretases, but the mechanism is not fully understood . In the present study, we examined the effect of inhibiting dynamin-dependent endocytosis on the activity of ADAM10 toward its substrate APP.
Although other ADAMs, notably ADAM17, are capable of cleaving APP, the expression of APP in adult mouse brain overlaps to a much greater extent with ADAM10 than with ADAM17 . Moreover, APP shedding is nearly abolished in primary neurons from mice null for ADAM10 , and in cell lines following knockdown of ADAM10 , indicating that ADAM10 is the physiologically relevant α-secretase in brain. Co-expression of ADAM10 with a dominant-negative dynamin mutant, dyn I K44A, increased surface expression of both mature and immature forms, indicating that endocytosis of ADAM10, like that of APP [16, 17] is dynamin-dependent. An earlier report showed that endocytosis of membrane-type matrix metalloprotease 1 (MT1-MMP) is inhibited by a dynamin K44A mutant, resulting in increased cleavage of its substrate pro-MMP2 . Thus, modulation of internalization could be a general mechanism regulating the activity of transmembrane metalloproteases toward their substrates.
Several laboratories have examined the effects of kinase activation on ADAM trafficking and protease activity. PMA caused down-regulation of ADAM17/TACE surface expression in Jurkat and THP-1 cells , and a transient increase followed by a decline in HeLa cells. The latter response was blocked by an inhibitor of mitogen-activated protein kinase kinase, and by mutation of threonine 735 to alanine of ADAM17/TACE . PMA also increased degradation of the mature processed form of ADAM17/TACE, but not ADAM10, in HEK293 cells , and promoted the translocation of ADAM10 to the cell membrane in glioblastoma cells . Taken together, the evidence indicates that PKC-regulated activation of ADAM10, or ADAM17/TACE, may be associated with alterations in trafficking in some cell types; however, neither PMA nor M3 receptor activation appear to regulate cell-surface expression of ADAM10 in HEK cells (Figure 3 and data not shown). Thus, the ability of these activators to promote APP ectodomain shedding in our model is not mediated by inhibition of internalization of either ADAM10, or its substrate APP .
Overexpression of ADAM10 increased constitutive, but not carbachol-evoked release of APP695 from HEK-M3 cells (Figure 3). Even in the absence of carbachol, surface APP695 was greatly reduced in ADAM10/APP695 co-transfectants (Figure 3), suggesting that under these conditions the response to carbachol is limited by the availability of APP695. This interpretation is supported by an earlier report, which showed that ADAM10 overexpression caused a much greater fold-increase in basal than in PMA-stimulated APP shedding from HEK cells, whereas a dominant negative ADAM10 mutant inhibited PMA-stimulated APP shedding by approximately 75% . Interestingly, surface levels of immature ADAM10, but not mature ADAM10, were increased in cells co-transfected with APP695, relative to levels in cells expressing ADAM10 and empty vector (Figure 3). This suggests that the association of APP with ADAM10 inhibits the processing of ADAM10 by proprotein convertases, but how or where in the cell this occurs is unknown.
In addition to increasing surface expression of ADAM10, the dynamin mutant caused a marked elevation in cellular levels of an ADAM10 CTF, the abundance of which was further increased by the γ-secretase inhibitor L-685,458 (Figure 4). This is consistent with earlier reports that ADAM10 is subject to proteolysis by ADAM9 or 15, generating a CTF that is a substrate for γ -secretase [19–21], and suggests that the cleavage of ADAM10 occurs at the cell surface. As with surface expression of ADAM10, generation of the ADAM10 CTF was not affected by carbachol (Figure 5), in contrast with an earlier report that PMA increases ADAM10 shedding in SH-SY5Y neuroblastoma cells . The reasons for this discrepancy are unclear, but could be related to cell-specific differences, which also appear to underlie the varying effects of PKC activators on ADAM10 trafficking. Because of the potential signaling role of the ADAM10 CTF  it would be of interest to identify factors that regulate generation of this fragment. One possible mechanism could involve alterations in ADAM10 endocytosis resulting from direct interactions with other cell surface proteins. An example of such a mechanism is the modulation of APP internalization and processing by members of the low-density lipoprotein receptor-related protein (LRP) family . Notably, binding to LRP1B retains APP at the cell surface, increasing its cleavage by α-secretase, and reducing Aβ generation [46, 47]. Similarly, F-spondin, a secreted signaling molecule implicated in neuronal development and repair , binds to both the APP ectodomain and the apolipoprotein receptor ApoE2, promoting sAPPα release, and inhibiting cleavage by β-secretase [49, 50]; both these effects are consistent with reduced internalization. We predict that binding partners of ADAM10 could affect its processing in a similar way.
Evidence from multiple laboratories indicates that amyloidogenic APP processing occurs in lipid rafts, whereas processing by ADAMs is confined to non-raft regions . Disruption of raft domains by depleting membrane cholesterol shifts APP processing in favor of non-amyloidogenic processing. This could reflect the displacement of APP from raft domains, and away from β- and γ-secretases [31, 51], but might also be due in part to inhibition of endocytosis . Although dynamin I K44A expression increased surface levels and ectodomain cleavage of mature ADAM10, there was no accompanying change in the partitioning of either full-length ADAM10 or its CTF in raft and non-raft domains (Figure 6). Thus, the effects of the dynamin mutant on ADAM proteolysis are likely simply to reflect the accumulation of ADAM10, and possibly of the ADAM that targets it, at the cell surface. To our knowledge, the effect of dynamin inhibition on the distribution of APP in membrane subdomains has not been addressed. However, like ADAM10 itself, the ADAM10 substrate N-cadherin underwent increased proteolysis in the presence of dyn I K44A, without altering its distribution between Triton-soluble and insoluble membrane domains (Figure 6C).
ADAM10 has numerous substrates , and alterations in its trafficking to or from the cell surface could affect its activity towards any or all of them, thereby regulating their biological activity. In the case of APP and N-cadherin, this could inhibit their ability to promote cell-cell adhesion, neuronal development and synaptogenesis [54, 55], but at the same time would increase the signaling functions of their liberated C-terminal fragments [35, 56]. Increased generation of the ADAM10 CTF, also a consequence of decreased internalization, might exert biological effects of its own , but these remain to be elucidated.
Our results demonstrate that the α-secretase ADAM10 is internalized by a dynamin-dependent mechanism. Inhibition of endocytosis by co-expression of a dominant negative dynamin mutant increased surface expression of ADAM10, and promoted its proteolysis, generating a prominent CTF. Neither surface expression nor proteolysis of ADAM10 was affected by activation of muscarinic M3 receptors, despite the ability of this PKC-coupled signaling pathway to robustly stimulate APP shedding. Inhibition of dynamin also promoted cleavage of the ADAM substrate N-cadherin, but did not affect the membrane localization of either ADAM10 or N-cadherin, which were associated predominantly with non-raft domains. It will be of interest to identify physiological factors that regulate ADAM10 internalization, as these have the potential to modulate cell-cell contacts mediated by ADAM substrates such as APP and N-cadherin, and to influence the generation and signaling functions of the CTFs of both ADAM10 and its targets.
Antibodies and other reagents were obtained from the following sources: 6E10 antibodies to sAPPα from Signet Laboratories (Dedham, MA), rabbit antibodies to the C-terminus of APP (APP-CT) from Zymed Labs (San Francisco, CA), mouse monoclonal antibodies to dynamin I and goat polyclonal antibodies to the ADAM10 prodomain from Santa Cruz Biotechnology (Santa Cruz, CA), rabbit antibodies to the C-terminus of ADAM10 from Chemicon International (Temecula CA), and mouse antibodies to the N-cadherin C-terminus from BD Biosciences (San Jose, CA). Goat anti-mouse IgG and goat anti-rabbit IgG peroxidase-conjugated secondary antibodies were from BioRad (Hercules CA). Mouse anti-goat/sheep IgG peroxidase-conjugated antibody was obtained from Sigma. Decanoyl-arg-val-lys-arg-chloromethylketone (Dec-RVKR-CMK) and [(2R, 4R 5S)-2-Benzyl-5-(Boc-amino)-4-hydroxy-6-phenyl-hexanoyl]-Leu-Phe-NH2 (L-685,458) were purchased from Bachem Bioscience (King of Prussia, PA), Mini-gels and reagents for electrophoresis were obtained from BioRad (Hercules CA), and PVDF (polyvinylidene difluoride) membranes were purchased from Millipore (Billerica, MA). 1,10-Phenanthroline, 2-mercaptoethanesulfonic acid, carbachol (carbamylcholine chloride) and PMA were obtained from Sigma-Aldrich (St. Louis MO). Sulfo-NHS-SS-Biotin was purchased from Pierce (Rockford, IL), Other reagents and materials were acquired from Fisher Scientific (Pittsburgh PA).
HEK-M3 cells (HEK cells stably transfected with M3 muscarinic receptors) were grown in Dulbecco's Modified Eagle Medium (DMEM)/F-12 supplemented with 10% fetal bovine serum (Invitrogen, Carlsbad CA) and maintained at 37°C in an atmosphere of 95% air, 5% CO2. The HEK-M3 cell line has been extensively characterized in our laboratory with respect to both M3 receptor signaling and APP metabolism [17, 30, 57, 58].
Plasmids encoding the following proteins were used for transient transfections: APP695 (a gift from Dr. Carmela Abraham), dyn I K44A (a gift from Dr. Marc Caron), HA-ADAM10 (a gift from Dr. Falk Fahrenholz) and N-cadherin (purchased from Origene Technologies, Inc., Rockville MD). Cells were transfected with the desired plasmid, or with an empty pcDNA3 vector, using LipofectAMINE Plus™ reagent (Invitrogen) according to the manufacturer's specifications. Experiments were carried out 48 h later.
Cell surface biotinylation
HEK cells were pre-incubated in serum-free DMEM for 1 h, and then washed in PBS, pH 7.9, supplemented with 1 mM Ca++ and 1 mM Mg++. To biotinylate surface proteins, the cells were incubated for 30 min with Sulfo-NHS-SS-Biotin (0.5 mg/ml in PBS, Pierce, Rockford, IL). Culture dishes were kept on ice and gently rocked during the incubation period. The biotin reagent was quenched by treating the cells with two 15 min washes of 50 mM glycine in PBS. Cells were rinsed again with PBS and lysed in a buffer containing 50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 2 mM AEBSF (4-(2-aminoethyl) benzenesulfonyl fluoride), 1 μ g/ml leupeptin, 1% (v/v) nonidet P-40, 0.05% (w/v) SDS, 0.5% (w/v) deoxycholate, and 10 mM 1,10 phenanthroline monohydrate. Lysates were incubated overnight with streptavidin-coated agarose beads (Pierce, Rockford, IL) at 4°C in a rotary mixer to isolate biotin-labeled proteins. These were size-fractionated on SDS gels, and analyzed by immunoblotting.
The protein content of cell lysates was measured using the bicinchoninic acid reagent (Sigma, St Louis CA). Medium was collected, cleared by centrifugation, desalted, lyophilized, and resuspended in SDS-PAGE loading buffer, as previously described . Lysates were centrifuged to remove insoluble material, and diluted in 6× loading buffer. Samples were normalized for protein content and size-fractionated on 7.5%, 10-20%, or 4-20% Tris-HCl mini-gels. Proteins were transferred to PVDF membranes, blocked for 2 h in 5%-powdered milk in Tris-buffered saline with 0.15% Tween-20 for 2 h, and probed overnight with primary antibodies. Membranes were washed and incubated with goat anti-mouse IgG, mouse anti-goat IgG or goat anti-rabbit IgG peroxidase-conjugated secondary antibodies and bands were detected using an enhanced chemiluminescence reagent (Pierce, Rockford IL). Approximate molecular weights were estimated using prestained standards from both BioRad (Hercules, CA) and Invitrogen (Carlsbad, CA). Membranes were imaged on a Kodak 440CF Image Station and quantitated using Kodak 1D Image Analysis software.
Preparation of detergent-resistant membrane fractions
Membrane fractions were prepared according to the method of Adam et al. . Briefly, cells were rinsed with PBS, suspended in buffer M containing 50 mM HEPES pH 7.4, 10 mM NaCl, 5 mM MgCl2, 0.1 mM EDTA plus protease/phosphatase inhibitor cocktail (Thermo Scientific), homogenized with 12 strokes in a Potter-Elvehjem tissue grinder, and centrifuged in a refrigerated microcentrifuge at 4°C for 5 min at 500 × g to pellet nuclei. The supernatant was decanted and centrifuged at 16,000 × g for 10 min at 4°C, the pellet was resuspended in buffer A (25 mM 2-(N-morpholino)-ethanesulfonic acid pH 6.5 and 150 mM NaCl) and then combined with an equal volume of buffer A containing 2% Triton X-100 and protease/phosphatase inhibitor cocktail. The samples were incubated on a rocking platform for 60 min on ice, then centrifuged at 16,000 × g for 20 min at 4°C. Supernatants were reserved as the Triton-soluble fraction. The pellet was rinsed with buffer A, resuspended in buffer B (20 mM Tris-HCl pH 7.6, 150 mM NaCl, 60 mM β-octylglucoside and protease/phosphatase inhibitor cocktail), and incubated on a rocking platform for 30 min on ice. The samples were centrifuged at 16,000 × g for 20 min at 4°C, and the supernatants collected as the Triton-insoluble fraction. Aliquots were assayed for protein content, and the remainder was diluted with 6× gel loading buffer and used for immunoblot analysis.
Data are reported as means ± the standard error of the mean (S.E.M). Data were analyzed by Student's t-test or by ANOVA (analysis of variance) and Fisher's Least Significant Difference test. Differences were taken to be significant at p < 0.05. Statistical analyses were carried out using Systat software version 5.2.1 (SPSS, Inc., Chicago, IL).
List of Abbreviations
amyloid β peptide
a d isintegrin a nd m etalloprotease
amyloid precursor protein
- dyn I K44A:
dynamin I K44A mutant
human embryonic kidney
protein kinase C
phorbol 12-myristate 13-acetate
secreted APP ectodomain.
The authors thank Dr. Falk Fahrenholz, Dr. Carmela Abraham, and Dr. Marc Caron for generously providing the expression plasmids used in this study. This work was supported by NIH grants MH59775, AG009525 and AG032709. RMC was supported in part by NIH training grant AG00115.
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