4th Dependence Receptor meeting: from basic research to drug development
Seminar organized by Patrick Mehlen (Apoptose, Cancer et Développement, CNRS UMR 5538, Centre Léon Bérard, University of Lyon, Lyon – France) and Dale E.Bredesen (Buck Institute for Age Research, Novato / University of California, San Francisco – USA) from 22 to 27 March, 2010.
Participants
Michèle Allouche, Clara V.Alavarez, Yves-Alain Barde, Graham Barrett, Agnès Bernet, Dale Bredesen (organizer), Marie Castets, Céline Delloye-Bourgeois, Joanna Fombonne, Varghese John, Noriaki Kitamura, Daniel Liebl, Fanny Mann, Patrick Mehlen (organizer), Yoshinori Murakami, Akira Nakagawara, Dwayne Stupack, Masahide Takahashi, Servane Tauszig-Delamasure, David Tulasne, Keqiang Ye
Abstract
The fourth meeting on dependence receptors featured descriptions of previously unknown dependence receptors. New mechanistic data were presented on the switch between the trophic, antiapoptotic response with the proapoptotic response that occurs with loss of trophic support. The possibility that the loss of trophic support may also involve the binding of an active antitrophin was also discussed. New in vivo data were presented on the rôles of dependence receptors in development, angiogenesis, oncogenesis, and neurodegeneration, as well as new therapeutic approaches based on dependence receptor fonction. The next meeting on dependence receptors is scheduled for 2012.
Report
Références de parution de ce compte rendu dans Science Signaling : Sci. Signal., 25 January 2011 Vol. 4, Issue 157, p. mr2 [DOI: 10.1126/scisignal.2001521]
On March 23-26, at Fondation des Treilles near France’s Cote d’Azur, scientists met at the 4th International Dependence Receptor Meeting, to discuss recent findings and new implications of research into the biology of dependence receptors. First described in 1993, these receptors play fondamental rôles in processes as disparate as development, oncogenesis, and neurodegeneration. Studies of dependence receptors have forced a reconsideration of receptor physiology: the classic view held that transmembrane receptors are activated by binding their respective ligands, but are relatively inactive when unbound. However, dependence receptors médiate programmed cell death in the absence of their ligands, but following ligand binding, support cell survival. Thus the expression of these receptors creates a State of dependence or addiction of the expressing cells on the trophic ligands. Furthermore, sub-apoptotic events such as cellular atrophy and process retraction may also be mediated, depending on cell type and developmental State. These receptors are thus bi-functional: in the presence of their ligands, they transduce a “positive” signal including activation of the classic signaling pathways such as MAPK or PI3K-dependent pathways; whereas, in the absence of their ligands, they are not inactive but rather trigger a “négative” signal, leading to programmed cell death or sub-apoptotic events such as process retraction or cellular atrophy (1) (2). As a network, these receptors may create an integrating, analog-to-digital converting unit, essentially a biochemical analogue to the electrical integration provided by the System of synaptic inputs.
To date, 17 such receptors have been identified, and these include the prototypical netrin-1 receptors DCC and UNC5H (UNC5H1, UNC5H2, UNC5H3,and UNC5H4), neogenin, RET, TrkC, Alk, EPHA4, Patched, Met, APP, p75NTR, the androgen receptor, and some integrins. The ramifications of the dependence receptor theory are numerous: for example, the expression of dependence receptors ties cells to a specific context which the ligand is available, and therefore may serve to block metastatic spread of neoplasms or growth beyond local ligand availability (3). Another example of dependence receptor effects is the médiation of developmental cell death in cells that do not receive trophic factor support. Thus dependence receptors often play an apparently dual role as tumor suppressors and mediators of neuronal development. More, such dependence receptor-mediated cell loss has also been implicated in neurodegeneration (4, 5). Thus dependence receptor mutations have been associated with disease States that include tumor formation, metastasis, developmental neuronal loss and neurodegeneration (6, 7).
The purpose of the meeting at les Treilles was to bring together scientists studying dependence receptors, in order todiscuss the pros and cons of the overall concept, potential new dependence receptors, proposed mechanisms of action and the potential therapeutic avenues in development through this concept.
New insight into dependence receptor-mediated cell death
Dale E. Bredesen (Novato, CA, USA) and Patrick Mehlen (Lyon, France) summarized the current view of dependence receptors (DRs) and the mechanisms by which they trigger apoptosis. The definition of dependence receptors is based on the observation that cells depend on various trophic influences for survival, such as diffusible trophic factors, extracellular matrix factors, cell-cell interactions, electricalactivity, and other inputs; and cells respond to the loss of such support by activating programmed cell death or, alternatively, other regressive responses such as synapse loss, process retraction, and cellular atrophy. The receptors that mediate these responses, and thus create a State of dependence on the trophic influences, are defined as dependence receptors.
The following pattern is emerging from mechanistic studies of dependence receptors (2, 6): (1) most dependence receptors interact with, activate, and are substrates for, caspases, the cysteine aspartyl-specific proteases that mediate apoptosis; (2) mutation of the caspase site(s) in dependence receptors results in a loss of the pro-apoptotic effect; (3) in at least some cases, the monomeric dependence receptor forms an apoptosis-mediating complex, whereas multimerization blocks the formation of this complex; (4) in at least some cases, apoptosis induction via dependence receptors proceeds via caspase-9 (unlike death receptors, which mediate apoptosis following ligand binding, via caspase-8 or -10), utilizing a novel pathway that is independent of the previously described caspase-9 activator, Apaf-1; (5) caspase cleavage of dependence receptors results in fragments that include one or more pro-apoptotic addiction/dependence domains (ADDs). Since dependence receptors recruit caspase zymogens that are relatively but not completely inactive, and are cleaved to yield pro- apoptotic fragments, such receptors may serve as caspase amplifiers in the absence of ligand binding. However, this view, although well supported by in vitro studies, may be only part of the mechanism by which DRs induce apoptosis. A discussion ensued on the requirement for caspase cleavage of dependence receptors for their pro-apoptotic activity, and, although it was acknowledged that some new candidate receptors may have been missed due to their lack of such sites (e.g., TrkA, as pointed out by Yves Alain Barde (Basel, Switzerland)), it was also apparent that caspase cleavage sites are not necessary for such receptors, as exemplified by integrin-mediated apoptosis following the withdrawal of extracellular matrix interaction (8). Thus other mechanisms may also exist to trigger apoptosis, such asmodulation of phosphorylation, as has been described for Unc5H-induced apoptosis mediated by DAP kinase (9). The Présence of caspase cleavage sites may indeed have led to a bias in the selection of the currently studied DRs, since in some studies it was utilized as part of a screen to select candidate DRs.
In support of this point, Yves Alain Barde (Basel, Switzerland) presented exciting data on TrkA and TrkC, showing in both cases the induction of apoptosis in the presence of inadequate concentrations of trophic ligand (NGF forTrkA andNT-3 forTrkC), both in embryonic stem cell-derived neurons and in vivo. Interestingly, TrkC was initially described as a DR a few years ago by Mehlen’s group on the basis of its ability to trigger apoptosis; however, at that time, the similar effect of TrkA was not studied further precisely because of its resistance to caspase cleavage. Barde’s findings indicate the fine tuning and the critical nature of the match-up between neurotrophin availability and neurotrophin receptor expression—even relatively modest mismatches may lead to apoptosis induction. His findings may also have important evolutionary implications: why were some receptors selected to display a caspase cleavage site (e.g., TrkC), while other, closely related receptors (here, TrkA) were not? One might speculate that the caspase cleavage site offers an amplifying step in caspase activation, but this remains to be demonstrated by acareful study mixing cell biology and evolution. Overall, however, the major points ofthe death mechanisms presented above were supported and extended by the new data presented during the meeting.
Several talks addressed this cell death mechanism, offering new insight into dependence receptor function: A. Nakagawara (Chiba, Japan) and M. Takahashi (Nagoya, Japan) presented intriguing data on the netrin-1 receptor UNC5H4 and the GDNF receptor RET, respectively, suggesting that the addiction/dependence domains (ADDs) of UNC5H4 and RET, released after caspase cleavage, are imported into the nucleus and trigger gene transcription.
Fombonne (Lyon, France) described the recently published work on the dependosome: this complex, shown to be recruited by the ADD of Patched (Ptc), was shown to include the adaptor proteins DRAL and TUCAN, as well as caspase-9. This complex, upon ligand withdrawal, was shown to trigger a DRAL-TUCAN-dependent caspase-9 activation, providing further support for earlier claims that dependence receptors may activate caspase-9 in an Apaf-independent fashion (10). M. Castets (Lyon, France) described the effort to determine new mediators of UNC5H2-induced apoptosis by performing a siRNA screen. This allowed the implication of the phosphatase complex PP2A in mediating UNC5H2-induced cell death by regulating the autophosphorylation of the serine threonine kinase death-associated protein kinase (DAPK). K.Ye (Emory,USA) also describe the implication of P1KE in the regulation of UNC5H2-induced apoptosis(11). D.Tulasne (Lille,France) presented related work showing that the dependence receptor Met, which is a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF) that has been implicated in multiple tumor types, undergoes caspase cleavage at Aspl000 in the juxtamembrane region; however, this cleavage is blocked by phosphorylation of TyrlOOl, preventing recognition by caspases, and cell death signaling via Met(12).
G. Alvarez (Santiago de Compostela, Spain) presented her work on another receptor tyrosine kinase dependence receptor, RET, and described the implication of a pathway including JNK and the transcription factor Pit-1 in the death mediated by the ADD of RET in the somatotroph cells of the pituitary gland (13). She also presented intriguing data on RET and its co-receptor GFR 2 in the possible stem cell niche of the Pituitary(14).
Roles of dependence receptors in vivo
A substantial part of the meeting was devoted to the roles played by dependence receptors in physiological processes, such as development, and pathological processes, such as oncogenesis and neurodegeneration. P. Mehlen and D.Bredesen described schematics of how DRs may be implicated in the control of these processes: with respect to embryonic development, because of the ability to trigger apoptosis in settings of limited ligand availability, DRs were hypothesized to control cell numbers in specific areas of the developing brain, and to demarcate territories of neuron migration and axon projection by eliminating those cells and processes that strayed from the ligand-demarcated path. For example, netrin-1 receptors mediate not only the chemotropic effect of netrin-1 in the developing nervous System, but also the survival of olivary neurons (15). Moreover, netrin-1 acts as a survival factor for spinal cord commissural neurons, both in primary neuron cultures and in vivo (16). Similarly, sonic hedgehog (Shh), the ligand of the DRPtc, is not only a morphogen, but also a survival factor (17, 18), inhibiting the pro-apoptotic function of Ptc, a function crucial for adequate neural tube development (10,19).
In related neural development studies, M. Takahashi (Nagoya, Japan) presented an impressive piece of work on the role of the pro-apoptotic activity of RET during neural crest migration. Knock-in mice were generated in which the caspase cleavage site of RET was mutated in order to prevent its pro-apoptotic activity. Despite the finding that this point mutation failed to affect the kinase signaling of RET, it led to a Hirschprung-like phenotype, with reduced migration of enteric neural cells. RET thus appears to be critical for the migration of neural crest cells that colonize and form the enteric nervous System and, in human and mouse models, mutations of RET have been associated with a partial to total aganglionosis. Interestingly, in agreement with the view that DRs control the number of migratory neurons, the D707N mice showed an increased number of neurons in the proximal intestine, representing the initial phase of neural crest cell migration, while the number of enteric neurons fell off with increasing distance along the gastrointestinal tract.
Another example of the role of dependence receptors during nervous System development was given by Y.A. Barde, who described TrkA and TrkC as mediators of neuronal cell death in settings in which their respective ligands were insufficient to support survival. He utilized neuronally differentiated embryonic stem cells in which TrkA or TrkC had been knocked into the tau site, and showed that, not only was programmed cell death induced in the cultured neurons, but when mice were created from these embryonic stem cells, the entire nervous System was destroyed rapidly and synchronously following TrkA or TrkC expression. Not only do dependence receptors mediate developmental neuronal cell death, they also affect non-neural cells:
M. Castets (Lyon, France) showed that the pair netrin-l/UNC5H2 is central for developmental angiogenesis by regulating survival/death of endothelial cells (20). This resuit suggests that autocrine expression of netrin-1 engenders the survival of metastatic tumor cells not only by inhibiting apoptosis, but also by fostering their vascular support.
Beyond the physiological cell death that accompanies development, and the selective, darwinian neoplastic cell turnover that hones metastases, increasing evidence supports the view that dependence receptors also play crucial roles in the neurodegenerative process. G. Barrett (Melbourne, Australia) complemented his earlier work, in which he showed that cell death induced by nerve growth factor (NGF) withdrawal could be prevented by antisense knock-down of the common neurotrophin receptor p75NTR, by evaluating the role of p75NTR in the central nervous System. Mice null for p75NTR displayed an increase in cholinergic markers— but not absolute neuronal number—in the basal forebrain, as well as cellular hypertrophy, an increase in cholinergic fibers, and an increase in hippocampal long-term potentiation, all suggesting that p75NTR inhibits septo-hippocampal function. Crossing the p75 nulls with Alzheimer model mice improved the memory performance of the Alzheimer model mice.
D. Bredesen also addressed the role of dependence receptors in neurodegeneration. In collaborative work between the Bredesen and Mehlen laboratories, the amyloid precursor protein, APP, was shown to function as a dependence receptor {Lourenco et al., 2009), with a trophic ligand (netrin-1), a single caspase site required for apoptosis induction (Asp664), and caspase-derived pro-apoptotic peptides (Jcasp and C31). Interestingly, APP has also proven to bind an anti-trophic ligand, which competes with netrin-1, as well as other trophic ligands. This effect labels the amyloid-betapeptide as the first “anti-trophin,” and suggests that the accumulation of this peptide in Alzheimer’s disease may indeed trigger an anti-trophic State in Alzheimer’s disease, with resultant synaptic loss, neurite retraction, and ultimately neuronal death. In addition to their roles in neurodegeneration, dependence receptors may also play a role in neural trauma: D. Liebl (Miami, FL, USA) recently reported that the nephrin receptors EPHA4 {Fume, 2009 #1024) and EPHB3 (21) acts as a dependence receptor in the subventricular zone of the adult brain. He described impressive data reporting the possible role of the ligand-receptor pair EphrinB3/EPHB3 in controlling neuronal survival after traumatic brain injury.
Using animal models, he showed that either by perfusing more ligand or by inactivating the respective dependence receptor, he could increase neural stem/progenitor cell survival (21). This, in turn, lead to protection of the motor cortex from progressive cellular loss, and resulted in improved motor locomotion.
Another critical role for dependence receptors in pathological States is the regulation of tumor progression. The dependence receptor model predicts a role for such receptors as conditional tumor suppressors— ie. tumor suppressors in the presence of limiting ligand concentrations, but oncogenic receptors in the presence of high ligand concentrations (22)—due to their ability to promote cell death when disengaged from their ligands. A tumor cell subjected to an environment with reduced trophic support (e.g., highly proliferative cells in an environment with limited ligand concentration or metastatic cells migrating to sites where ligand is absent) would displayunbound dependence receptors and thus undergo apoptosis. This mechanism may represent a protective mechanism to limit tumor Progression. It is therefore predicted that, in aggressive tumors, such rapid proliferation or metastasis would require inactivating this dependence receptor-mediated safeguard, either via mutation of the receptor or via autocrine expression of the trophic ligand. Consistent with this view, A. Bernet (Lyon, France) described previous data and ongoing work demonstrating the loss of DCC and UNC5H in human colorectal cancer, complemented by results from mouse models showing that netrin-1 and its receptors regulate intestinal tumorigenesis (22) (23) (24).
One of the most well-known, yet poorly understood, phenomena in oncology is the spontaneous regression that occurs frequently in neuroblastoma, stage IV-S. Data collected by A. Nakagawara suggest that this phenomenon is mediated by the dependence receptor Unc5H4, potentially as a result of the reduction in circulating trophic support that occurs early in postnatal development. Nakagawara showed that Unc5H4 is a positive prognostic marker in neuroblastoma, and that it is markedly up-regulated in stage 1V-S, spontaneously regressing neuroblastoma.
He therefore proposed Avery attractive model in which, in stage IV-S, regression is due to up-regulation of UNC5H4, triggering apoptosis. Conversely, TrkB is a marker of poor prognosis, and it was pointed out during discussion that, coupling this finding with those ofY. Barde(who showed that TrkA and TrkC, but not TrkB, induce apoptosis in the setting of reduced ligand concentration), one might consider TrkB as an “independence receptor” that confers survival on expressing neuroblastoma cells independent of any development-associated reduction in ligand availability.
Work from D.Stupack (SanDiego, CA, USA)echoed this point, and described other functional markers of neuroblastoma behavior, as well: for example, as neuroblastoma cells migrate and lose integrin ligation, they are induced to undergo apoptosis by dependence receptors such as the 1integrin (25). Moreover, loss of this integrin increase invasiveness and metastatic potential. Interestingly, caspase-8 co-localizes with integrins and its expression is lost in approximately 70% of neuroblastomas, typically either through deletion or methylation. While this reduces dependence on integrin ligation, it also reduces migration and adhesion: caspase-8 displays multiple tyrosine phosphorylation sites and is phosphorylated by src family kinases, allowing it to bind the src SH2 domain, displace calpastatin from calpain, thus activating cal pain, which cleaves talin, effecting a six-fold increase in the affinity of talin for integrins, and enhancing migration. Surprisingly, this calpain-activating effect of caspase-8 does not require proteolytically active caspase-8( 26).
The identification of novel dependence receptors Similarly to DCC and UNC5H, a cell adhesion molecule called CADM1/TSLC1was also shown to bea tumor suppressor(27).
Y. Murakami (Tokyo, Japan) thus proposed that it could act as a novel type of dependence receptor, regulating cell death and tumor progression by acting as both a ligand and a receptor-i.e., by interacting in trans with itself.
As noted above, Y.A. Barde reported TrkA as a mediator of neural cell death in the presence of mismatched (Le., reduced relative to receptor expression) concentrations of NGF, and proposed that TrkA and TrkC trigger apoptosis via a secretase cleavage of the co-receptor p75NTR.
M. Allouche(Toulouse,France)described the receptor tyrosine kinase Alk (anaplastic lymphoma kinase), which has been implicated in lung tumors, lymphomas, and neuroblastomas (28), as a dependence receptor (29), even though, to date, no reliable ligand has been described invertebrates for this receptor.
G. Delloye-Bourgeois (Lyon, France) showed preliminary data supporting the rôle of GDO as a novel dependence receptor for sonie hedgehog (SHH). CDD, which resembles DCC, was recently identified as a SHH receptor that participates in the transduction of the Ptc signal,and C. Delloye-Bourgeois showed that CDD undergoes caspase cleavage in the absence of SHH, thus exposing a pro-apoptotic domain. In agreement with the common dual implication of dependence receptors in oncogenesis and neural development, she then showed that CDO is critical for the development of the branchial arch, and acts as a tumor suppressor in multiple tumor types.
F. Mann (Marseille, France) made an intriguing observation with a receptor known to be implicated in axon guidance: she showed convincingly that Plexin DI is a dependence receptor for the semaphorin Sema3E, and provided evidence that this ligand-receptor pair plays an important rôle in breast cancer metastasis.
Toward drug development targeting dependence receptor pathways Re-activating proapoptotic pathways in humancancer cells is one of the major current strategies in the development of cancer therapeutics. Therefore, dependence receptors may
represent promising targets for cancer treatment, and work presented at the Les Treilles meeting supports that approach. However as noted above, in various cancers these dependence receptors-e.g., Ptc, DCC, UNC5H, ICAD, and CDO—arelost or reduced in expression, which may provide a selective advantage for tumor growth. In such tumors, targeting dependence receptors is unlikely to provide benefit. However, A Bernet described that, in a large fraction of neuroblastomas, lung cancers, and metastatic breast cancers, the selective advantage observed is not a loss of dependence receptor expression, but rather a gain of the autocrine expression of netrin-1. She showed that, in these tumors, interference between netrin-1 and UNC5H induces apoptosis of tumor cells in vitro, and leads to tumor regression in vivo, in multipleanimal models (30) (31) (32). She also described the pre-clinical development of candidate drugs interfering with the netrin-l-UNC5H interaction.
Furthermore, other trophic ligand-dependence receptor loops may also represent therapeutic targets: S. Tauszig-Delamasure (Lyon, France) showed that NT-3 is also up-regulated in neuroblastoma and breast cancer, and that intereference between NT-3 and TrkC interaction is associated with tumor cell death in vitro and tumor growth inhibition in multiple animal models (33). Similar results were presented for CDO and Plexin DlbyC. Delloye-Bourgeois and F. Mann, respectively, thus supporting the view that targeting ligand-dependence receptor interactions may indeed represent a productive approach to cancer therapeutics.
Since, as noted above, accumulating evidence suggests that dependence receptors also play a role in the neurodegenerative process, V. John (Novato, CA, USA) presented initial work targeting APP as a dependence receptor mediating Alzheimer’s disease pathogenesis. Given the recent failures of several therapeutic candidates for Alzheimer’s disease, a new approach like that described by V. John may be timely.
As he explained, just as for other dependence receptors, APP functions as a molecular switch: when bound by its anti-trophic ligand, A, APP is proteolytically cleaved at three sites, generating four peptides—sAPP, A, Jcasp, and C31—that mediate neurite retraction, synaptic re-organization, and ultimately programmed cell death (7).
Conversely, when bound by its trophic ligand, netrin-1 (note that APP also interacts with other ligands such as somelaminins and collagens, F-spondin, and others), APP is proteolytically cleaved at two sites, generating three peptides—sAPP, p3, and AICD— that support synaptic maintenance and inhibit programmed cell death. Thus one drug discovery approach has been to screen for “switching drugs,” which switch APP processing toward the three supportive peptides and away from the four pro-apoptotic peptides. Initial small molecules have been identified that demonstrate such an effect.
Summary
This fourth meeting on dependence receptors featured descriptions of new dependence receptors such as TrkA, EPHA4, CDO, plexinDl, and ICAD/TSLC1; new mechanistic data on the switch between the trophic, anti-apoptotic response, and the loss of trophic support, pro-apoptotic response, as well as the possibility that the loss of trophic support may also involve the binding ofan active anti-trophin; new in vivo data on the roles of dependence receptors in development, angiogenesis, oncogenesis, and neurodegeneration; and new therapeutic approaches based on dependence receptor function. The next meeting on dependence receptors is scheduled for 2012.
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ldiebold (11 août 2010). 4th Dependence Receptor meeting: from basic research to drug development. Les carnets de la Fondation des Treilles. Consulté le 10 novembre 2025 à l’adresse https://doi.org/10.58079/14gzz

