1. Introduction
In mechanistic terms, endocytosis is the process by which plasma membrane (PM) components, together with extracellular solutes, macromolecules and particles, are internalized in the cell. Once the endocytic vesicle (or vacuole) is formed by fission of the PM, it is generally delivered to a specialized membrane compartment – the endosome – for recycling, degradation or re-routing.
In cell-physiological terms, endocytosis exerts multiple functions, which are only partially known and characterized. At a minimum, it maintains PM homeostasis by counterbalancing the apposition of new membrane (due to exocytosis) and by renewing PM components. More extensively, endocytosis constantly modulates PM composition and takes an active part in a variety of normal and pathological cell processes, including cell nutrition, cell motility, mitosis, neurotransmission, immune response, and microorganism entry (reviewed in [1-8]).
1.1. Endocytosis and signaling
In recent years, much of the effort to investigate this extensive endocytic activity has been focused upon unveiling the reciprocal interplay between endocytosis and cell signaling. In this introductory section, we provide a quick overview of the key concepts in the field to explain the endocytic function in Notch signaling. We refer those readers who wish to explore the relationship between endocytosis and cell signaling in details to other papers in this volume, and to recent reviews in the field [3, 9-11].
Originally, endocytosis was linked to the termination of PM-generated signals by reducing the availability of membrane receptors for ligand binding, and by degrading the ligand-receptor complex (reviewed in [10, 12-14]). Hence, blockage or dysregulation of endocytosis closely correlates with increased cell proliferation by the activation of receptor-tyrosine kinase pathways and cancer promotion (reviewed in [10, 15, 16]). More recently, new strategies for the endocytosis-mediated regulation of signaling have been uncovered: (i) endocytosis can activate/modulate some PM-generated signals either directly (e.g. by controlling ligand availability, as in the case of the cell-to-cell Eph/Ephrin signaling pathway [17]), or indirectly (e.g. by regulating the composition of specific signaling platforms, as in the case of phospholipase C and PI3Kinase signaling activated via EGF receptor [18]); (ii) endocytosis can propagate signals to intracellular compartments, especially the endosomal compartment, where these signals are sustained, specified, spread over long distances or rerouted (reviewed in [9, 19-22]); (iii) endocytosis can ensure spatial restriction to signaling responses emanating from the PM and/or from the endosome (e.g. the endocytosis/recycling function in the spatial restriction of signaling controlling migratory programs (reviewed in [23], or in determining the timing, levels, and localization of guidance receptors, thus determining the outcome of guidance decisions [24]). On the other hand, signaling can modulate endocytosis: (i) activation of specific signaling pathways can upregulate or downregulate endocytosis, thus modulating other PM- and/or endosome-generated signals (e.g. EGF receptor activation increases SRC kinase-mediated phosphorylation of the clathrin heavy chain, which redistributes to the cell periphery, potentiating endocytosis [25]); (ii) actin dynamics/signaling takes an active part in the endocytic reaction by helping membrane invagination [26, 27], vesicle transportation [28, 29], and endosomal microdomain organization [30]. We will see that many of these endocytic strategies to control signaling are exploited in Notch signaling.
1.2. Types of endocytosis and their regulation
In order to promote its many functions, endocytosis relies on a variety of specialized mechanisms and accessory factors to guarantee selectivity, vectoriality and plasticity.
Regarding these mechanisms, there are multiple forms of endocytosis that act concomitantly in the cell (reviewed in [4, 31-33]). The best studied, and perhaps the most common, forms are clathrin-based. Their central paradigm is the recruitment and assembly of clathrin to the PM, triggered by a variety of adaptor proteins, which bind (and sometimes bend) the PM by means of lipid- and protein-interacting domains (reviewed in [34]). Invagination of the PM to form a bud depends on a concerted action of the clathrin lattice rearrangement (which shapes the high curvature profile of the bud [35]), polymerization of bending proteins (which shape the neck of the bud (reviewed in [36])), and actin polymerization (which helps the extension and constriction of the neck of the bud [37, 38]). Constriction of the bud and its fission to form free clathrin-coated vesicles requires the pinchase action of the GTPase dynamin(s) (reviewed in [39-41]). Free vesicles are then stripped of their coat by an uncoating complex, composed of the ATPase heat shock cognate 70 (HSC70) [42] and the J-domain-containing co-chaperone auxilin [43]. Structural requirements for the uncoating reaction are reviewed in [44, 45]. An essential function is also carried out by phosphoinositides, and more specifically by the PtdIns(4,5)P2 present in the membrane of coated vesicles, which has to be hydrolyzed by synaptojanin for efficient release of endocytic adaptors, which precedes clathrin disassembly [46, 47].
Clathrin-mediated endocytosis (CME) is not the only type of endocytosis. It is now many years since evidence for clathrin-independent endocytosis (CIE) has been accumulated, although the mechanism behind this process is as yet poorly characterized. The development of specialized techniques, reagents and markers to trace endocytosis has unveiled a whole new world of internalization routes that persist after inhibition of the clathrin function (reviewed in [32, 48-50]). A common finding is the exquisite sensitivity of CIE to cholesterol depletion, although CME is also somewhat sensitive to cholesterol levels, and some forms of CIE can still occur without membrane cholesterol [51]. On the PM, cholesterol is transiently enriched in microdomains, commonly known as lipid rafts [52]. This fact, together with the absence of rafts in clathrin intermediates and with the observation that most of the raft components are endocytosed by non-clathrin-dependent pathways, has led to the idea that most CIE occurs in these lipid microdomains. At rafts, signaling events are subcompartmentalized in specific nanoplatforms, whose composition and, therefore, activity is continuously changing [52]. The wealth of proteins that participate in raft signaling events also gives rise to a number of different CIE pathways which differ for (i) fission machinery (i.e. dynamin-dependence), (ii) coat composition and (iii) Rab effector specificity (reviewed in [4, 32, 50]). Both CME and CIE forms participate in Notch signaling activation and regulation.
Regarding accessory factors, tens of molecules, both proteins and lipids, interact with endocytic machinery at various stages. Several recognition modules have been identified, including protein-lipid (e.g. PH domain) and protein-protein interaction modules (e.g. BAR, SH3-, proline rich-, EH-, coiled-coil domains, ubiquitin interacting motifs (UIM)). It is conceivable that this array of interactions may help regulate both CME and CIE by: (i) assisting coat assembly/disassembly, (ii) regulating membrane shaping/sculpting and fission, and (iii) mediating interaction of the coat with signaling molecules and the cytoskeleton (reviewed in [4, 9, 34, 53-55].
In this review, we will focus on the molecular details at the basis of the endocytic control of Notch activation. Specific emphasis will be made on genetic data in mammals and invertebrates that support or validate
2. Overview of the Notch signaling pathway
The first Notch gene was identified in
The Notch signaling is a cell-to-cell communication pathway that is activated when Notch ligands (
2.1. Domain structure of Notch components
Let us now briefly analyze the architecture of Notch receptors and ligands to highlight those structural features that are key factors in endocytosis-mediated signaling activation (reviewed in [80, 81]).
While
2.1.1. Notch receptor architecture
Notch receptors are multidomain proteins, which have been conserved from invertebrates to man. Going from the N- to the C-terminus, mammalian Notch receptors contain five regions (Fig.1): (i) a variable number of
2.1.2. Notch ligand architecture
As for Notch receptors, Notch ligands are genes that have been conserved throughout evolution.
2.2. Notch ligand-receptor interaction
In the last few years, major advances have been made in clarifying the structural details of Notch-DSL interaction. This information is highly relevant to understand the effect of internalization and membrane trafficking on Notch signaling activation.
2.2.1. Structural requirements
By screening
2.2.2. Glycosylation function
Post-translational modifications play a key role in modulating Notch activation. NECD is heavily glycosylated and many studies have tried to address the impact of these modifications on Notch signaling.
A proteinIn
The precise role played by Pofut1 in this process was partially addressed by creating a mouse mutant bearing a Notch1 allele which was deficient for the fucosylation in a critical EGF-like repeat for DSL binding, i.e. EGF-12: trans-heterozygous mice carrying the Notch112f allele and a Notch1 null allele exhibit embryonic lethality, and defects similar to Notch1 knockouts [120]. However, homozygous Notch112f mice are viable, but with defects in T cell specification and functions and, notably, a sharply decreased binding capacity to Delta1-expressing cells [120], thus pointing to a key function of fucosylation in regulating the affinity of Notch receptors for Notch ligands.
Quite recently, experimental evidence has accumulated for other key roles of Ofut1 besides fucosylation. In
Gene knockdown of the
Regarding the extension of
In addition to fucosylation, Notch receptors are also modified by
Therefore, genetic and in vitro data on Notch glycosylation indicate (i) that
3. Endocytosis in notch signaling activation
An absolute requirement for endocytosis was an early finding in Notch studies. Notably, the
Localization studies of Notch and Delta during fly development showed that both Notch and Notch ligands were in a dynamic equilibrium between a PM pool and an intracellular vesicle pool, with a transition to internalized pool upon interaction of adjacent cells [154]. Delta is detected at both the PM and in vesicles only at some stages of specific developmental systems, while it is mostly internalized in others, including all stages and cell types of retinal development [154-158]. Morphological analyses of Delta subcellular localization in this latter development system have clarified that most, if not all, Delta-containing vesicles have an endocytic origin [159, 160]: Delta is re-localized to the PM in the full endocytic mutants,
Thus, the paradigm in the field is that Notch signaling critically depends on DSL endocytosis for its activation and modulation. We shall now analyze the molecular machinery involved in this process. At present, as the reader will see, only partial information is available, with (many) puzzling and (some) conflicting results.
3.1. Notch ligand endocytosis
The molecular characterization of DSL endocytosis began to attract great interest when it was published an in-depth morphological analysis of the effect of the
However, direct evidence that NECD shedding by endocytosis is required to trigger the Notch proteolytic cascade was lacking in the
3.1.1. Mechanistic models
Following the staminal observation by Parks et al. [165], many laboratories investigated the machinery and the types of endocytosis that are at the basis of DSL-mediated Notch activation. A large collection of data has been produced which points at two distinct, but not mutually exclusive, models (see Fig.2): (i) according to the “pulling force” model (that derives directly from the observation of NECD shedding [165]), DSL internalization can exert a mechanical stretching, or detaching, action on the NECD to unmask the cleavage sites (especially S2) of Notch receptors; (ii) alternatively (“Notch ligand/DSL trafficking model”), or in combination with the previous model, an inactive DSL is activated either by trafficking through a recycling compartment (“ligand maturation” or “recycling” model), or by transcytosis to a membrane domain where interaction with Notch receptor occurs with increased frequency (“highly polarized cells” model).
It is plausible that, if (and/or when) the two models combine, they will act sequentially: DSL activation by intracellular trafficking should precede the mechanical shedding of the Notch receptor by DSL endocytosis, making the two mechanistic models not just compatible, but even synergistic.
The initial hint for the existence of a trafficking event that could activate the Notch ligand in order to make it competent for Notch activation came from the analysis of the fly mutant
An important question on the “ligand maturation” model regards the nature of the DSL activation process. In the
Intracellular trafficking can also activate DSLs with another mechanism, i.e. by re-localizing DSL from a membrane domain where it cannot interact with Notch to a membrane domain where this interaction can efficiently occur. This “highly-polarized cell” model is supported by at least two key sets of experiments undertaken in the
A universal requirement for DSL trafficking does not seem exist for all tissues or developmental systems. Rab11 function, which was found to be essential for Delta trafficking and activation in the SOP system, is not required for
More recently, the emerging structural findings described in section 2.2.1 have steered and re-focused the attention on the “pulling force” model. Direct evidence supports this model. As already discussed, using classical techniques to study membrane trafficking events it was possible to demonstrate that DSL-mediated receptor dissociation precedes and permits the proteolytic activation of Notch both in flies and in mammalian cells [87, 165]. A better structural appreciation of this event was acquired by using a material science technique to study surface morphology at the atomic level. Atomic force microscopy, applied to protein (or other molecules) interactions, can quite precisely measure the force applied to make contact between two interacting surfaces (the contact force) and the force applied to detach them after contact (the detachment force). This technique was then adapted to measure cell-cell adhesion [191] and was used to characterize Notch interaction [192]. A specific setup was engineered to mount a single S2-Delta-expressing
Since Notch proteolysis proceeds constitutively after exposing the S2 cleavage site (either by shedding of the Notch ectodomain or through its stretching), this unmasking reaction has to be considered the true rate limiting step of Notch signaling activation [196]. What are the structural constraints that keep S2 in an inactive silent state, preventing unwanted activation before ligand interaction? How are these constraints lifted/eased/modified during Delta-mediated NECD pulling? As anticipated in section 2.1.1, experimental evidence points to the NRR region of NECD for this key inhibitory action of Notch cleavage. Receptors that lack EGF-like repeats cannot undergo constitutive proteolytic cleavage and are functionally inert [70, 94, 108, 197-199]; conversely, an NTMD construct undergoes constitutive cleavage to release NICD [87]. Taken together, these data indicate that the restraints on ligand-independent activation of Notch receptors reside in a region downstream of EGF-like repeats but upstream of NTMD. This region corresponds to the three LNR repeats plus the HD domain, i.e. the NRR (see Fig.1). Key evidence to support this idea came from the isolation of Notch gain-of-function or loss-of-function phenotypes directly related to the NRR. (i) Antibodies raised against the NRR region did not compete with ligand binding to the receptor, but strongly inhibited Notch activation [96, 200]. Notably, those inhibitory antibodies recognized a conformational epitope lying on a face where the first LNR repeat (LNR-A) approaches the β-sheets of the HD (HD2), supporting the idea that autoinhibition is due to the clamp of LNR1 and HD2 together (see later for structural considerations) [96]. Conversely, an anti-Notch-1 antibody that recognized a linear epitope in the LNR1 domain only was activating Notch signaling, possibly by inducing a conformational change of the LNR1 that opened the access to the S2 site [96]. (ii) Mutations in the NRR of Notch receptors produced gain-of-function phenotypes in various biological contexts, including invertebrate developments. An activating mutation of the
Many structural data have been collected in recent years that have helped to clarify the mechanistic details of NRR function, in particular (i) the NRR role in protecting S2 from constitutive cleavage and (ii) the kinetics of S2 autoinhibition. At present, the crystal structure of the NRR of human Notch-1 [88], of human Notch-2 [98], and the co-crystal of inhibiting antibodies, together with their target NRR epitopes [204], have been solved at high resolution. The NRR of Notch-2, the first NRR analyzed, was seen to form a very compact structure with overall dimensions of 60Åx45Åx25Å [98]. The three irregularly folded LNRs wrap around the HD domain forming “a cauliflower-like shape, in which the LNRs 'florets' cover and protect the HD domain 'stem'” [98]. The two halves of the HD domain, (i.e. the HD-N before the S1 site and HD-C after this site, see Fig.1) form an intimately intertwined α/β sandwich containing three α-helices and five β-strands connected by several conserved loops [98]. The inner, concave face of the HD domain has hydrophobic residues pointing toward its center. The S2 site is on the β5-strand of the HD-C and it is actually buried in a small pocket that prevents protease accessibility; the pocket is formed by the hydrophobic residues of α-HD -C and of the LNR-AB linker. In particular, it is thought that a leucine residue (L1457) extends from the LNR-AB linker toward a critical valine residue (V1666) at the C-terminus of the S2, thus obliterating the access to the ADAM cleavage site [98]. The α3-helix above the S2 site is stabilized by hydrophobic interactions with residues in the LNR-B and in the LNR-AB linker plus a conserved hydrogen bond from LNR-A [98]. Consistent with previous structural data, deletion of LNR-A, the LNR-AB linker and LNR-B makes a constitutively activated Notch-2 [98]. The Notch-1 NRR structure is similar, although not identical, to that of the human Notch-2 NRR, with the classic conformation of the LNR-AB linker providing a key leucine residue that packs tightly against the C-terminal valine of the S2 site. As for NRR2, the folding of the HD domain has a rather stiff structure that is stabilized by extensive interaction between helices and strands. These data confirm a common autoinhibition strategy that is implemented among Notch family members [95].
Additional and fundamental structural data on Notch NRR function and dynamics came from the field of Notch immunotherapy and from the application of unconventional structural techniques. In an effort to overcome problems generated by the clinical use of presenilin inhibitors to silence the Notch pathway (in particular, the lack of selectivity for this pathway with a consequent broad toxicity), phage display technology was used to generate highly specific antibodies that could selectively antagonize a single Notch paralog (i.e. able to distinguish between Notch-1 and Notch-2) [204]. A co-crystal of this interaction shows that inhibitory, anti-NRR1 Fab-fragments bridge the LNR and HD domains, thus locking the NRR in a clamped conformation, which makes the S2 site unreachable for metalloproteases [204]. Further key data for the understanding of NRR-dependent S2 activation came from the application of hydrogen exchange mass spectrometry, a technique that monitors the exchange of deuterium between the solvent and the backbone amides during conformational changes [205, 206]. More specifically, when a surface of a protein is exposed it is rapidly deuterated, while when it is masked the exchange of hydrogen for deuterium is slow, or it does not happen at all. This technique was used to monitor the accessibility of the S2 cleavage site in a condition which should mimic ligand-dependent Notch activation, i.e. by chelation of Ca2+, a condition which causes the dissociation of the Notch receptor and triggers its signaling [207] (although widely used, Ca2+ chelation cannot be considered a surrogate of DSL action on the Notch receptor but obvious experimental constraints prevented the use of a more physiological condition). The results of these experiments showed that (i) upon Ca2+ chelation, LNR-A unfolding was the first event to occur, followed by the unfolding of LNR-B; (ii) after unfolding of the first two LNRs, the S2 site became accessible to the external environment, thus confirming previous results with deletion mutants in which removal of the LNR-A and LNR-B regions was sufficient to obtain a constitutively activated receptor [98]; (iii) Ca2+ is fundamental in stabilizing the secondary structure of LNR repeats [98]; (iv) HD-N and HD-C do not separate when S2 is exposed, and the HD domain maintains its folding for a very long time after Ca2+ chelation (i.e. well beyond the proteolytic cleavage of the receptor is terminated). This latter observation may indicate that ectodomain shedding is not an absolute prerequisite for the activation of the Notch proteolytic cascade [97]. To summarize, these structural data suggest that LNR-A and –B repeats are the fundamental gatekeepers of Notch activation as they control access to the Notch S2 cleavage site. Interestingly, in a recent paper, topology-based coarse-grained and physics-based atomistic molecular dynamics simulations were used to predict the conformational changes that occurred in the NRR by intrinsic and force-induced mechanisms [208]. These computer simulations showed that LNR unfolding is not sufficient to unmask the S2 site, but the continuous application of an external stretching/pulling force is needed to unfold the HD domain and, in particular, its β-5 strand [208]. Notably, the extension force required to unfold the β5 strand should be much lower than the force needed for heterodimer dissociation [208], suggesting that dissociation of Notch receptor is not needed for its activation, since an intermediate state with exposed S2 site might persist for a significant period of time before global unfolding and heterodimer disassociation occur. These predictions provide new and unforeseen roles for HD in Notch activation that definitely need experimental support.
3.1.2. Specialized endocytic machinery
Genetic evidence in invertebrates and mammals points to ubiquitylation (also referred to as ubiquitination) as the master regulatory mechanism controlling the endocytosis implicated in Notch signaling activation (reviewed in [209-211]).
Ubiquitylation, i.e. the conjugation of ubiquitin to proteins, is a rather common post-translational modification that regulates protein stability, localization, and activity (reviewed in [9, 11, 212-215]). Ubiquitin is a small conserved protein, whose C-terminal glycine (Gly76) can be engaged in a covalent isopeptide bond with the ε-amino group of lysine residues in substrate proteins. Ubiquitin can serve as an acceptor to form a polyubiquitin chain via one of its seven lysine residues (K6, K11, K27, K29, K33, K48 and K63). A hierarchical set of three enzymes acts in a sequential process to operate ubiquitin modification: (i) ubiquitin-activating (E1), (ii) -conjugating (E2), and (iii) -ligating (E3) enzymes. The large numbers of the latter enzymes (of which, the best studies are the
The first hint that ubiquitylation might be a necessary step for Notch activation came from the correlation between two sets of data, obtained almost twenty years apart: (i) a mutation screening in
Since then, an impressive number of experiments has been carried out on Neuralized activity and action in invertebrates. Key advances can be summarized as follows. (i) The RING domain was found to be critically required for Delta endocytosis: as expected, when the mutant
In mammals, two neuralized-like genes, Neurl1 and Neurl2, are present. Quite surprisingly, inactivation of these genes does not result in major phenotypic defects [240-242]. Only subtle defects were scored in Neurl1-/- mice: (i) male mutants are sterile due to a defect in the axonemal organization of spermatozoa that leads to immotile sperm [242]; (ii) female KOs are defective in the final stages of mammary gland maturation during pregnancy [242]; (iii) Neurl1-/- mice are hypersensitive to ethanol effects on motor coordination and exhibit a defect in olfactory discrimination [241]. Only these latter defects can be putatively connected to an impairment of some subtle (yet to be defined) function of Notch in mammalian neurons, but no classical Notch signaling defects are identifiable in these mutants. Clearly, a compensation by the remaining Neurl2 gene was suspected, but, surprisingly and unexpectedly, inactivation of both Neurl1 and 2 did not result in any overt Notch defect in mice [240].
Neurls are not the only Notch-ligand specific E3 ligases present in vertebrate genomes. Another family, named after its first member
Inactivation of Mib1 in mice finally results in a pure Notch phenotype, which recapitulates the most severe mammalian mutants of this signaling pathway [240]. Surprisingly, triple Neurl1/Neurl2/Mib2 knockout mice do not show major phenotypic defects, suggesting that Mib1 is the only essential E3 ligase for Notch activation. In support of these genetic data, knockdown of mib1 expression by siRNA dramatically reduces Notch activation in mammalian co-culture experiments [247, 248].
Activation of DSL internalization by ubiquitin moieties requires UBDs recognition and functional binding. Genetic experiments in mammals and invertebrates point to epsin family members as the principal actors in linking endocytosis, ubiquitylation and Notch activation. Epsins are highly conserved genes with two homologues in yeast (Ent1, Ent2) [249], one in Drosophila (Lqf) [250], and three epsin genes (Epn1, 2 and 3) in mammals. While epsins 1 and 2 are expressed in all tissues [251, 252], epsin 3 is restricted to surface epithelia [253, 254]. Epsins have a characteristic, highly conserved, three domain structure: (i) a
Genetic studies in invertebrates have shown that the only epsin gene present in these species is required for the activation of Notch signaling [171, 245, 271, 272], and that this function is closely related to DSL ubiquitylation [245]. Genetic experiments in mammals have confirmed those studies and firmly established the essential role of epsin1 and 2 in Notch activation in vertebrates [273]: (i) the absence of epsin1/2 expression during mouse development correlates with embryonic lethality at midgestation, with multiorgan defects highly reminiscent of the most severe Notch mutants; (ii) accordingly, expression of Notch primary target genes is severely reduced in epsin1/2 double knockout embryos. Surprisingly, housekeeping forms of clathrin-mediated endocytosis were not impaired in cells deriving from those embryos [273].
A very recent study has provided evidence that epsins might have a previously unforeseen role in membrane fission [274]. In particular, predictions based on biophysical models support the idea that amphipathic helices (as those present in the epsin ENTH domain) could create a higher energy state due to their limited insertion into the polar head region, but not into the hydrocarbon region of the PM. This accumulated energy, when released, will crucially favor the fission reaction. This hypothesis was carefully tested
Taken together, these experiments suggest that epsins are the best candidates to explain the molecular action of ubiquitylation in DSL endocytosis, although the machinery behind this function has still to be fully uncovered. Triple epsin knockout mice could be the key to shed light on this molecular network.
Regarding the types of endocytosis, most of the evidence cited in section 3.1 strongly supports a clathrin-dependent pathway for DSL uptake. However, in invertebrates and, more specifically, in their oogenesis, Delta endocytosis could occur in an AP-2- and clathrin-independent way, as assayed by Notch activation of surrounding follicular cells triggered by germline clones bearing mutations of clathrin and AP-2 adaptor subunits, but not dynamin [190]. In the same system, it was also analyzed the dependence of Notch activation on endosomal trafficking in signal-sending cells: germline clones mutant for small GTPases that critically regulate the endosomal compartment, including Rab5 and Rab11, normally activate Notch in follicular cells. Taken together, these data support the absolute requirement for dynamin in DSL uptake. Conversely, neither CME nor endosomal entry of DSLs are universally required for Notch activation [190] (and, see section 3.1.1).
3.2. Notch receptor endocytosis
As discussed at the beginning of section 3, a strict requirement for endocytosis in the signal-receiving cell is supported by
3.2.1. Notch receptor internalization and PM-emanating signals
Some recent results seem to question the requirement of Notch receptor internalization for the activation of its signaling. In mammalian HeLa cells, overexpression of a dominant negative form of dynamin (the K44A mutation) does not prevent the processing of a chimeric NEXT to generate the NICD, which then translocates to the nucleus and activates signaling [275]. Blockage of the internalization step increases γ-secretase-mediated Notch processing and downstream signaling, suggesting that Notch receptor endocytosis might tame the Notch signaling emanating from the PM, as observed for other signaling pathways (see section 1).
This puzzling result is supported by other observations both
In the same set of experiments on HeLa cells, the machinery responsible for Notch internalization was also partially characterized. It was found that Notch uptake is strictly dependent on clathrin, since it is suppressed by knockdown of this latter gene and of its adaptor AP-2, while it is attenuated in the absence of epsin1 [275]. Notably, epsin1 interaction with Notch was ubiquitin-dependent, and the HECT domain-containing E3 ligase Nedd4 was found to participate in that action [275]. In the
To summarize, these data suggest that, in specific cell systems, PM emanating signals (from Notch receptors) can be (down)regulated by endocytosis, which uses the same machinery of the Notch signal-sending cell, i.e. clathrin-mediated endocytosis triggered by ubiquitylation with a role of epsin in coat formation and membrane invagination (and perhaps fission). The suppressive action of endocytosis on Notch activation can have many functions, including the termination of Notch signaling and the cell-fate determination of the Notch signal-sending cell, as Numb function seems to suggest (see next section).
3.2.2. Notch receptor trafficking and endosomal-emanating signals
In elegant morphological experiments, Notch receptor localization, processing, and signaling output in subsequent steps of its endocytic route were monitored by analyzing imaginal discs in
In a search for factors that regulate Notch activation in endosomes, it was found that mutations of the vacuolar proton pump (V-ATPase) produce defects in the processing of the internalized Notch receptor and its signaling [281, 282]. These results, together with the observation that presenilin works optimally in an acidic environment such as that present in the endosome/lysosome [283], support the idea that endosomal sorting of Notch is required for best activation of its S3 cleavage. However, unrestricted access of Notch receptors to the endosome should be prevented, since the acidic pH could dissociate the NECD, thus triggering ligand-independent Notch activation [210].
Another somewhat newer protagonist in Notch activation from endosomes is Deltex, whose mutation results in a lethal phenotype when associated to a gene dosage defect of one of the DSLs or Notch. Deltex encodes for a highly conserved gene endowed with three domains (reviewed in [284]): (i) a N-terminal WWE domain which binds the ANK repeats of Notch, (ii) a central proline-rich region for the binding to yet unknown SH3 domain-containing proteins, and (iii) a C-terminal RING-domain which has the signature of an E3 ligase, yet formal evidence of a Deltex direct ubiquitylation of Notch is lacking [284]. All domains are necessary for Deltex function, whose action has been studied intensively in recent years.
Data support a Deltex action both in Notch internalization and activation. Evidence for these functions can be summarized as follows: (i) in the
However, the positive or negative outcome of endosomal sorting on Notch activation depends on other regulatory factors that control or antagonize the action of Deltex. (i) A member of the Nedd4 family of E3 ligases,
A key aspect of Notch signaling is the need to establish differential signaling between two cell populations, i.e. the signal-receiving cells in which Notch activation can be triggered and the signal-sending cells in which Notch activation is suppressed. In invertebrates, Notch expression at the cell surface of the signal-sending cell is dramatically downregulated in order to inactivate Notch signaling in this cell population. One way of obtaining this effect is to target the Notch receptor to endosomal degradation with a specialized machinery. During the first division of the SOP, a membrane-associated protein called Numb is asymmetrically partitioned in the pIIb cell, which is committed to become the Notch signal-sending cell [295]. Loss of
Since Numb can co-exist with Notch in some cell systems without antagonizing its function (as in the lateral inhibition of
Another key interactor of Numb is Spdo, which is expressed in flies in both the Notch ligand-bearing and Notch receptor-bearing cells, where it acts differentially: in neuroblast division, Spdo is required for the activation of the Notch receptor in the A cell (a cell with Notch-dependent fate) [305] while in the B (signal-sending) cells it stimulates the endocytic degradation of the Notch receptor, in concert with Numb [305]. Notably, Numb in pIIb (signal-sending) cells of SOP induces the endocytosis of Spdo in early and late (but not recycling) endosomal vesicles. As for Numb internalization, Spdo endocytosis requires α–adaptin both in SOP [307] and in the neuroblast divisions in the flies [298]. As a result of
4. Conclusions
In 2013, it will be one hundred years since the first Notch gene was discovered. During this century, fundamental aspects of gene functioning have been uncovered, including the key molecular mechanisms involved in the normal and pathological activation of Notch signaling. What emerged is that endocytosis is the master regulator of Notch activation. This function is exerted by means of a specialized endocytic machinery, which acts differentially in the Notch signal-sending cell compared with the Notch signal-receiving cell.
In Notch signal-sending, genetic, cell biology, structural, and biophysical studies point to a mechanical action of the Notch ligand on its receptor, so that critical proteolytic sites are uncovered for constitutive activation. Although the molecular machinery has not been fully characterized, genetic evidence in vertebrates and invertebrates supports clathrin-mediated endocytosis of ubiquitylated DSLs, as being the key mechanism that exerts the pulling action on the Notch receptor. In some developmental and cell culture systems, trafficking of the Notch ligand by transcytosis is another crucial mechanism which exerts the fundamental action of locating the Notch ligands in PM domains, where the interaction with the Notch receptor occurs with the highest efficiency. Evidence in specialized developmental systems in invertebrates supports a third function of endocytosis in the Notch signal-receiving cell, where DSL trafficking through the recycling endosome may serve the purpose of making Notch ligands competent for interaction with Notch receptors. However, the molecular event that pre-activates the Notch ligand is unknown, and no evidence has been provided yet to support a similar request in mammalian cells.
In comparison with the Notch signal-sending cell, where an endocytosis requirement is well established and many molecular details of its action are known, very little information is available, especially in vertebrates, to help us understand the need for endocytosis in the Notch signal-receiving cell. Genetic and cell-biology studies suggest that Notch signaling preferentially spreads from the endosomal compartment, where the acidic environment favors the γ-secretase release of the Notch active fragment (i.e. the NICD). As in the signal-sending cell, ubiquitylation is requested for this process, and its modulation by a variety of factors either firmly localizes Notch in a membrane trafficking compartment for signal activation, or quickly moves it to lysosomes for signal suppression.
Although we are beginning to see the “the big picture”, crucial mechanisms are still missing. Although incomplete, some of the available endocytosis-related information has already entered medical experimentation [309]. A clear example is γ-secretase inhibitors (GIS), whose action is exploited in many current clinical trials for T-ALL, breast carcinoma, colon cancer, medulloblastoma, glioblastoma, osteosarcoma, pancreatic cancer, small-cell lung carcinoma, and melanoma, just to cite some of these studies. Analyses of GIS have also been extended to basically all cell lines and animal models in which a function of Notch for tumor promotion, progression and spreading was not only proved, but merely supposed. However, GIS use in current medical practice is far from established since the molecules that have so far been tested are plagued by significant human toxicity involving gastrointestinal bleeding and immunosuppression, which is attributable to widespread suppression of Notch signaling in many tissues. As discussed throughout this review, Notch actually plays a key role in the homeostasis of a variety of adult tissues, and its suppression thus hampers the functionality of many organs and systems. More unconventional approaches of Notch-related therapy are based on raising inhibiting or activating antibodies that regulate the level of Notch signaling by interfering with the Notch ligand-Notch receptor interaction, and, consequently, by directly or indirectly affecting the endocytic regulation of Notch signaling. Some of these antibodies are already in the initial phases of clinical trials, and they promise to offer better selectivity in targeting specific Notch components, thus minimizing side effects.
Notch-targeting therapies have a wide potential spectrum of application besides cancer, which includes developmental, vascular, cardiac, and other diseases associated with Notch pathway malfunction, or where Notch function could be exploited profitably for their treatment. It is not difficult to envisage a future interest for a highly-specific “endocytic-based” therapeutic approach to Notch dysregulation.
Acknowledgement
We thank Michael John for critically editing this review and Lorenzo Cremona for the artwork. Our work is supported by grants to OC from Ministero dell'Istruzione dell'Università e della Ricerca Scientifica (MIUR - PRIN2008 grant), Fondazione Cariplo, Fondazione Telethon (grant GGP10099), and Associazione Italiana per la Ricerca sul Cancro.
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