Feb 22, 2010 - On the Death Trk. Liraz Harel, Barbara Costa, Mike Fainzilber ..... Shimada H, Nakagawa A, Peters J, Wang H, Wakamatsu. PK, Lukens JN ...
On the Death Trk Liraz Harel, Barbara Costa, Mike Fainzilber Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel
Received 8 September 2009; revised 27 October 2009; accepted 28 October 2009
ABSTRACT: The trk family of receptor tyrosine kinases supports survival and differentiation in the nervous system. Paradoxically it has also been shown that members of the trk family can induce cell death in pediatric tumor cells of neuronal origin. Moreover, TrkA and TrkC serve as good prognostic indicators in neuroblastoma and medulloblatoma, respectively. Although the possible linkage between these observations was intriguing, until recently there was limited insight on the mechanisms involved. Recent findings suggest that TrkA might influence neuronal cell death through stimulation of p75 cleavage. An alternative p75-independent mechanism was suggested by a newly discovered interaction between
The neurotrophins are critical regulators of cell survival in the nervous system, exerting their effects via two types of receptors, the trk family of receptor tyrosine kinases (RTK) and the shared p75 neurotrophin receptor. Trk receptors are well-established mediators of neurotrophin dependent prosurvival signaling (Huang and Reichardt, 2003). Paradoxically, TrkA and TrkC have also been reported to induce cell death in certain cell types. Death induction has been reported for a few other RTKs (Ancot et al., 2009), but those studies have remained controversial and the molecular mechanisms whereby trks or any other RTKs induce death are not well understood (Chao, 2003). Correspondence to: Mike Fainzilber (mike.fainzilber@weizmann. ac.il). Contract grant sponsors: Israel Science Foundation, M.D. Moross Institute for Cancer Research, European Union Endocyte Research and Training Network, Chaya Professorial Chair in Molecular Neuroscience at the Weizmann Institute of Science. ' 2010 Wiley Periodicals, Inc. Published online 22 February 2010 in Wiley InterScience (www. interscience.wiley.com). DOI 10.1002/dneu.20769
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TrkA and CCM2 (the protein product of the gene cerebral cavernous malformation 2). Coexpression of CCM2 with TrkA induces cell death in medulloblastoma and neuroblastoma cells, and CCM2 expression levels correlate with those of TrkA and with good prognosis in neuroblastoma patients. Thus, mechanistic clues to the enigma of trk-induced cell death have begun to emerge. Detailed elucidation of these mechanisms and their in vivo physiological significance will be of keen interest for future research. ' 2010 Wiley Periodicals, Inc. Develop Neurobiol 70: 298–303, 2010
Keywords: Trk; p75; neurotrophin; CCM2; neuroblastoma
Trks and Prognosis in Pediatric Tumors of Neural Origin The enigma of trk-induced death has been of particular interest in the study of pediatric tumor cells of neural origin. Neuroblastomas are pediatric solid tumors derived from the sympathoadrenal neural crest lineage (Nakagawara, 2004). Many of the infants diagnosed with neuroblastoma before one year of age undergo complete regression of the disease, whereas older children frequently have metastatic tumors that are extremely refractory to currently available therapy (Brodeur, 2003; Brodeur et al., 2009). A number of early observations even suggested that initial neuroblastoma foci actually arise far more frequently in young infants than the number of clinical reports, again indicating a high rate of regression of the disease at very young age (reviewed in Nakagawara, 2004). This striking dichotomy in disease outcome fueled an intensive search for markers of prognosis, and a flurry of initial studies quickly linked TrkA expression to early and regressing stages of neuroblastoma (Borrello et al., 1993;
On the Death Trk
Donovan et al., 1993; Kogner et al., 1993; Suzuki et al., 1993; Iwata et al., 1994; Kogner et al., 1994; Brodeur, 1995). This link has been confirmed in many studies over the past 15 years, establishing full length TrkA as one of most robust indicators of positive prognosis in neuroblastoma (reviewed in Brodeur, 2003; Shimada et al., 2004; Brodeur et al., 2009). It should however be noted that a less widely expressed alternatively spliced non-NGF responsive variant, TrkAIII, has negative effects on prognosis (Tacconelli et al., 2004; Farina et al., 2009). Although neuroblastoma arises from peripheral neural precursors, medulloblastomas are malignant tumors of the central nervous system in children (Ullrich and Pomeroy, 2003). Like neuroblastoma, medulloblastoma can be subdivided to a number of subtypes with differing prognosis (Johnsen et al., 2009), including a nodular/desmoplastic subtype containing \islands" of cells with round nuclei and abundant cytoplasm. Localized expression of TrkA or TrkC has been detected in such islands, in parallel with concentrations of apoptotic or differentiating cells (Eberhart et al., 2001; Ohta et al., 2006). An early study linked TrkC to positive outcome in medulloblastoma (Segal et al., 1994), and although the correlation is less dramatic than for TrkA in neuroblastoma, additional work over the past years has established TrkC as a positive prognostic indicator in medulloblastoma (reviewed in Gulino et al., 2008).
Trk-Induced Death in Medulloblastoma and Neuroblastoma Cells The clinical findings stimulated studies on likely mechanisms that could explain the link between trk receptors and positive prognosis. An initial experiment by Virginia Lee and coworkers examined the effects of stably transfecting TrkA into two medulloblastoma cell lines. Surprisingly, NGF treatment of TrkA-medulloblastoma cells caused significant levels of apoptosis (Muragaki et al., 1997). NGF application to wild type medulloblastoma cells or to p75 or TrkC expressing cells had no effect on viability. The death effect was inhibited by K-252A, an inhibitor of TrkA phosphorylation; and likewise was abolished in kinase-dead or signaling tyrosine mutants of TrkA, as well as by a dominant-negative Ras inhibitor (Chou et al., 2000). Pomeroy, Segal, and coworkers carried out a detailed study on TrkC effects in medulloblastoma, and showed that NT-3 stimulation induced death of primary tumor cells in culture under serumfree conditions (Kim et al., 1999). Apoptosis was highly correlated with TrkC expression levels in
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primary medulloblastoma, and transfection of TrkC in the Daoy medulloblastoma cell line inhibited the growth of intracerebral xenografts in vivo (Kim et al., 1999). As with the Lee group studies, K252A blocked the trk-induced death; however in contrast to Chou et al. (2000), pharmacological inhibitor experiments suggested that p38MAPK activity was required for TrkC-induced apoptosis (Kim et al., 1999). TrkCexpressing medulloblastomas did not spontaneously regress despite increased cell death in the tumors, suggesting that the rate of TrkC-induced apoptosis usually does not overcome tumor cell proliferation in vivo (Kim et al., 1999). Taken together, these findings suggested that trk signal transduction pathways can activate apoptotic cell death programs in medulloblastoma cells both in vivo and in vitro. The effects of trk receptor transfection and neurotrophin ligand challenge in neuroblastoma have been less clear cut than in medulloblastoma, perhaps due to the diverse range of neuroblastoma lines used in different studies. Receptor expression levels (Yan et al., 2002) and differing subtype expression profiles (Bassili et al., in press) have also been proposed as explanations for the diversity seen in cellular responses in vitro. Nonetheless, Lucarelli et al. (1997) showed that TrkA-transfected clones of N15 neuroblastoma cells exhibited a significant reduction in proliferation in response to NGF, while treatment of TrkB-transfected clones with BDNF had no effect. A decrease in neuroblastoma cell number was reported in another study from the same group, due to a TrkA-mediated decrease in N-myc expression (Woo et al., 2004). More recently, Kaplan and coworkers showed that virally mediated expression of TrkA induces apoptosis in two neuroblastoma cell lines, via a mechanism dependent on p53 and caspases (Lavoie et al., 2005). Another study reported apoptotic death of neuroblastoma SK-N-MC cells engineered to express TrkA under a tetracyclineinducible promoter (Jung and Kim, 2008). Taken together, these studies suggest that the prognostic link of TrkA to positive outcome in neuroblastoma may be due to a death-inducing activity of the receptor.
Trk-Induced Death in Other Cell Types Apart from neuroblastoma and medulloblastoma, trk family members have been implicated in death pathways in a handful of other cell types. Expression of TrkA in a rat glioma cell line reduced its invasiveness and transfected cells revealed a higher rate of apoptosis (Lachyankar et al., 1997). Interestingly, although apoptosis has been implicated in most other studies Developmental Neurobiology
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on trk-induced death in neural tumor cells, a recent study in TrkA-transfected human glioblastoma cells suggested an autophagic death mechanism (Hansen et al., 2007). Autophagy is executed by lysosomal degradation, and has important roles in cell homeostasis under diverse conditions in the nervous system (Tooze and Schiavo, 2008). Stable cell lines of human TrkA in glioblastoma G55 responded to NGF with marked cytoplasmic vacuolation and subsequent cell death. Caspase activation and apoptosis markers were not seen, rather the authors identified autophagic vacuoles by electron microscopy, and showed occurrence of a number of hallmarks of autophagy (Hansen et al., 2007). A mix of apoptotic and autophagic cell death mechanisms was reported in TrkAtransfected U2OS osteosarcoma cells (Dadakhujaev et al., 2009). TrkA overexpression in U2OS cells leads to caspase-7 activation and production of truncated BAX, in parallel with autophagosome formation and LC3 lipidation. Furthermore, depletion of autophagic effectors such as Atg5 or Beclin1 inhibited TrkA-induced cell death in U2OS cells (Dadakhujaev et al., 2009). Taken together, the group of papers summarized above strongly support a role for induction of death by trk receptors in different tumor cells. This is in stark contrast to the usually reported survival supporting effects of trks in neurons. Intriguingly however, sporadic reports have also implicated trk receptors in induction of cell death in neurons. TrkA signaling was shown to prime dorsal root ganglion (DRG) sensory neurons for zinc-mediated cell death in culture, apparently by inducing or up-regulating the expression of an unknown zinc susceptibility factor in the neurons (Morley et al., 2007). TrkB signaling was suggested to potentiate the toxic effects of the environmental toxin methylmercury on primary cultures of rat cerebellar granular neurons, perhaps via synergized elevation of intracellular calcium (Sakaue et al., 2009). Another study reported that TrkC (but not TrkA or TrkB) induced caspase-dependent death upon transfection to HEK293T cells, and that this death did not require kinase activity of the receptor (Tauszig-Delamasure et al., 2007). Transfection of a caspase-resistant TrkC mutant into embryonic mouse DRG neurons concomitantly with siRNA-mediated downregulation of endogenous TrkC was reported to result in a greater number of surviving neurons after NT-3 withdrawal. The authors interpreted this result as supporting a proapoptotic role of endogenous TrkC in the absence of ligand, but did not clarify how the receptor might switch from survival-promoting to death-promoting activity in the same neuron immediately after ligand withdrawal (Tauszig-Delamasure et al., 2007). Developmental Neurobiology
Does TrkA Induce Death Via p75? Matrone et al. (2009) conducted a similar ligand withdrawal study as Tauszig-Delamasure et al. (2007), examining the effects of NGF withdrawal on embryonic hippocampal neurons in culture. Twentyfour hours after NGF removal they observed neuronal death accompanied by marked phosphorylation of TrkA on the Y490 Shc binding site, as well as an increase in p75 cleavage and beta amyloid peptide production. The TrkA re-phosphorylation was observed a long time after the reduced phosphorylation typically observed upon ligand withdrawal (Matrone et al., 2009). Neuronal cell death occurred concomitantly with the rephosphorylation, and both events could be blocked by anti-amyloid beta antibody or a and c secretase inhibitors, the latter apparently acting to inhibit cleavage of the p75 neurotrophin receptor in these neurons. Pharmacological inhibition of TrkA phosphorylation or partial silencing of TrkA and/or p75 receptors also protected the neurons from death (Matrone et al., 2009). Bronfman and colleagues have reported that TrkA activation can stimulate cleavage of p75 (Bronfman, 2007; Urra et al., 2007), and others have reported proapoptotic effects of p75 cleavage products in hippocampal neurons (Sotthibundhu et al., 2008; Volosin et al., 2008). The generality of TrkA induction of p75-mediated death remains to be determined, especially given the fact that TrkA and p75 expression ratios may vary markedly in hippocampal neurons under different physiological and pathological conditions (Brann et al., 2002; Matrone et al., 2009). Nonetheless, it is plausible that survival versus death outcome of a combined TrkA/p75 signaling system might hinge on regulation of proteolytic cleavage [Fig. 1(A)].
CCM2 Mediates TrkA Death Signaling in Pediatric Tumor Cells of Neural Origin Although a TrkA-induced p75 cleavage might well be the primary mechanism for TrkA modulation of cell death in neurons, the fact remains that p75 was not required for TrkA-induced death in different types of pediatric tumor cells of neural origin (see above). We recently discovered a new TrkA interactor that provides an entry point to non-p75-dependent cell death pathways. CCM2 (cerebral cavernous malformation 2) was shown to interact with a juxtamembrane site in TrkA (Harel et al., 2009). CCM2 is required for maintenance of vascular integrity in animal models (Kleaveland et al., 2009; Whitehead et al., 2009), and CCM2 mutations in humans cause cerebral cavernous malformations in the central nervous
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Figure 1 Two potential mechanisms for TrkA-induced cell death. (A) Matrone et al. (2009) suggested that TrkA instigates death of cultured hippocampal neurons after NGF withdrawal via a delayed phosphorylation that activates a signaling cascade leading to p75 cleavage mediated death. (B) Harel et al. (2009) described a new interaction between TrkA and CCM2, and showed that coexpression of both molecules induces death in pediatric tumor cells of neural origin. This mechanism required activated TrkA, but was not dependent on p75.
system (Akers et al., 2009; Pagenstecher et al., 2009). Although CCM disease-related phenotypes are most prominent in the vasculature, CCM2 is ubiquitously expressed in many cell and tissue types, including within the nervous system (Plummer et al., 2006). Coexpression of CCM2 with TrkA caused cell death in HEK293 and PC12 cells, and the activity required full length CCM2 and kinase active TrkA (Harel et al., 2009). Notably, there was no requirement for ligand, and the death effect occurred also in presence of serum, indicating that it was dominant over other survival or proliferation signals encountered by the cells. CCM2 knockdown attenuated TrkA-induced death in both medulloblastoma and neuroblastoma cells (Harel et al., 2009). Furthermore, TrkA and CCM2 transcript expression were highly correlated in tumors from a large cohort of neuroblastoma patients, and showed a striking link between increased CCM2 and TrkA expression and positive clinical outcome (Harel et al., 2009). Thus, CCM2 is a critical mediator of TrkA-induced cell death [Fig. 1(B)]. Strikingly, a chimeric mutant of CCM2, with replacement of its phosphotyrosine binding domain with that of Shc, could induce death with all three trk receptors (Harel et al., 2009). The CCM2 PTB domain interaction with TrkA is at a site lacking a tyrosine residue, arguing that CCM2 serves an adaptor or linker function rather than directly impacting on TrkA signaling. Indeed the functional interaction site on TrkA is a specific segment of the juxtamembrane domain implicated in receptor internalization and
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recycling (Chen et al., 2005), and transfer of this interaction site to TrkB conferred a death-induction gain of function with CCM2 (Harel et al., 2009). Thus, the CCM2-mediated switch of TrkA signaling from life to death might be via changes in subcellular localization or trafficking of the receptor. Further studies will be required to delineate all the steps in this pathway and to assess its impact on other receptors and other types of tumors. The identification of CCM2 as a primary effector of TrkA-induced death and its linkage to disease outcome in neuroblastoma may provide a molecular entry point for elucidation of the enigmatic mechanism of trk-induced death. Moreover, TrkB and TrkC are far more widely expressed in the central nervous system than TrkA (Holtzman et al., 1992; Merlio et al., 1992; von Bartheld and Fritzsch, 2006), thus it is intriguing to speculate that a CCM2-TrkA death pathway might play a role in early elimination of inappropriate or excess precursor cells in the CNS, perhaps similar to the effects of ephrin-EphA signaling on cortical progenitor cell apoptosis (Depaepe et al., 2005). Finally, the possibility of activating the death pathway with other receptors via chimeric mutants of CCM2 may have implications for the targeting of other types of cancer.
Open Questions It is well established that trk receptors support survival and differentiation in the nervous system. Here we have summarized a growing body of work that show that the trk family can also signal or enhance death of certain cell types, primarily pediatric tumor cells of neural origin. The mechanism(s) and physiological significance of trk death signaling remain poorly understood, and despite the very recent progress outlined above, many questions still remain to be answered. How and when do trks switch from survival-promoting to death-promoting activity? Do p75 and CCM2 represent distinct mechanisms favored in different cell types, or are they different facets of a many-sided pathway? Perhaps most intriguingly, does trk-induced cell death have a role in normal development of the nervous system? We look forward with interest to future answers to these questions.
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