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Endocytosis and Signaling: Cell Logistics Shape the Eukaryotic Cell Plan
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TP53 may also regulate the endocytic machinery through mechanisms that are independent from its role as a transcription factor. In fact, TP53 has been found to localize in the cytoplasm, mitochondria, and centrosomes reviewed in Ref. It was recently shown that TP53 binds to the clathrin heavy chain not only in the nucleus as we will discuss in sect. While the transcription-independent connection between TP53 and endocytosis needs further validation and independent confirmation, it might add to the nonnuclear functions of TP E3 substrates can therefore be monoubiquitinated when a single UB is appended , multiple monoubiquitinated when single UBs are appended to multiple sites , or polyubiquitinated when substrates are conjugated to a UB chain.
In addition, UB chains display different topologies, according to the linkages joining the various UB moieties in the chain. Here we will limit ourselves to the connections between UB and endocytosis, exclusively from the signaling perspective.
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Pioneering work in yeast has demonstrated that UB is required for the first step in cargo internalization, as well as for targeting cargoes to vacuoles the yeast equivalent of lysosomes , The molecular basis of UB-dependent regulation of endocytosis is being clarified. We will describe two reciprocal aspects of the process, namely, how signaling controls ubiquitination ligand-induced ubiquitination of receptors and of endocytic adaptors and how ubiquitination controls endocytosis, fate, and consequently signaling. Activation of signaling receptors can transmit signals to the ubiquitination machinery that then modifies the receptors themselves.
In both cases, CBL binds directly to phosphotyrosine pY -sites on the activated receptor through its NH 2 -terminal tyrosine kinase binding TKB domain , , as well as indirectly through its constitutive partner GRB2, which is recruited to receptors via other pY sites , , Once bound, the ligase is phosphorylated and consequently activated Figure 4.
The ubiquitin system and endocytosis. This induces ENaC endocytosis and lysosomal targeting, resulting in fewer channels at the cell surface g. D : RSP5 ubiquitinates permeases and transporters. In yeast, arrestin-related trafficking adaptors ARTs and the E3 UB ligase Rsp5 are recruited to the PM in response to environmental stimuli that trigger the endocytosis of proteins such as permeases and transporters e. The ubiquitinated cargo is then internalized and degraded k. ARTs are also ubiquitinated by Rsp5, an event required for endocytosis, though the mechanism remains unclear l.
E : ubiquitination of adaptors: ARR. F : ubiquitination of adaptors by EGFR. These adaptors, in turn, are ubiquitinated by NEDD4 through a process known as coupled monoubiquitination cU. Another class of E3 ligases, the HECT NEDD4 family , whose regulation has been extensively studied, also regulates endocytosis and sorting of numerous signaling receptors. Once again, the ligase appears to be regulated by its phosphorylation.
Finally, specific binding proteins can regulate the process of ubiquitination by acting as adaptors to recruit the E3 to receptors that lack a direct binding motif for the ligase reviewed in Ref. Similar to direct receptor ubiquitination, the ubiquitination of endocytic adaptors plays a critical role in endocytosis. MDM2-ARR binding occurs constitutively and does not persist after receptor activation, suggesting that UB modification might cause a conformational change on ARR required to promote internalization. ARR is not the sole example of endocytic adaptor subjected to UB modification.
Several components of the downstream endocytic machinery are modified by monoubiquitination upon RTK activation , , , What is the role of adaptor ubiquitination? Monoubiquitination might permit the formation of several tiers of ubiquitination-dependent interactions in the endosome, by allowing binding of ubiquitinated cargo through UBDs and recruiting another layer of UB receptors through a monoUb signal. The result would be signal amplification and progression of ubiquitinated cargoes along the endocytic pathway. This mechanism might in turn harbor a series of consequences, for instance, the release of ubiquitinated cargo that would thus become available for the next tier of interactions along the endocytic route.
A similar mode of regulation was proposed for RABEX-5, which despite not being an endocytic adaptor is also subject to coupled monoubiquitination , In this case, it was shown that monoubiquitination of RABEX-5 was sufficient to prevent its recruitment to endosomes In addition, it was recently reported that monoubiquitination of Vps27 vacuolar protein sorting 27, the yeast homologue of HRS , a component of ESCRT-0, is not required for cargo sorting along the degradative endocytic route In conclusion, while the relevance of the ubiquitination of endocytic proteins is clear in some cases, it remains obscure in others.
One possibility is that the simple idea of a general mechanism should be abandoned and that the role of ubiquitination in endocytosis be established on a per-case basis. This would not be inconceivable, given the extreme versatility and plasticity of ubiquitination as a regulator of protein function. For instance, a relatively unexplored aspect concerns the signaling properties of UB as a tool for the propagation of effector signals, something that might involve also endocytic proteins.
In this contention it is of note as also reviewed in sect. In this section, we will concentrate on the relevance of ubiquitination on 1 the internalization step of endocytosis and 2 the determination of fate at the endosomal level. While at the endosomal level the picture is reasonably well defined and most likely identifies a stereotyped and general mechanism to commit cargo to degradation in the lysosome, at the internalization step the situation is much more heterogeneous and, in some instances, still controversial. In mammalian cells, the situation is far more complex, and the regulation by UB often varies depending on the receptor system.
In many other cases, however, receptor ubiquitination does not seem to be essential for the internalization step while still being essential for sorting at the endosomal level. The fact that receptor ubiquitination is not indispensable for the internalization step, in the mentioned cases, does not imply that it has no role at all. Indeed, at least three different sets of observations should be taken into account to fully understand the liaison between ubiquitination and internalization in mammalian cells.
This is the case of RTKs where multiple docking sites for the internalization machinery have been identified. EGFR provides the best understood model: through the combination of biochemical, proteomic, and mutational studies, multiple endocytic signals have been identified in the intracytoplasmic moiety of the receptor These include linear recognition motifs [e.
Such a plethora of signals defines a probable scenario in which 1 optimal internalization requires cooperation of different signals and of their recruited pathways and 2 multiple layers of redundancy might be built in the system to ensure robustness.
Thus individual signals, such as UB, might not be indispensable, but still participate in the process under physiological conditions. In addition, different types of ubiquitination might direct the cargo to distinct endocytic routes. In these cases, therefore, it is the cargo-associated adaptor that provides the signal for ubiquitination.
In conclusion, it is becoming clear that ubiquitination regulates internalization via multiple mechanisms, which are frequently cargo-specific, and in some instances coupled to different entry portals. In addition, cells may have learned how to exploit cargo ubiquitination to add redundancy and robustness to their internalization.
Following internalization, ligand-induced ubiquitination plays a key role in the lysosomal targeting and downregulation of signaling receptors. This conserved machinery performs three distinct but connected functions: 1 it recognizes ubiquitinated cargoes and prevents their recycling and retrograde trafficking; 2 it deforms the endosomal membrane, allowing cargo to be sorted into endosomal invaginations; and 3 it catalyzes the final abscission breaking off of the endosomal invaginations, forming intraluminal vesicles that contain the sorted cargo for exhaustive reviews, see Refs.
Since the rate of receptor downregulation and MVB targeting typically correlates with the extent of receptor ubiquitination in endosomes, interference with this posttranslational processing enhances signaling, such as for mutants in EGFR ubiquitination sites Furthermore, genetic disruption of members of the ESCRT complexes, which are required for membrane fission events, including those that lead to endosomal intraluminal vesicle formation, leads to sustained EGFR signaling in mice 35 , , and, in Drosophila , to NOTCH hyperactivation and neoplastic transformation This latter observation underscores the emerging involvement of endosomal sorting, and endocytosis in general, in tumorigenesis for recent reviews, see Refs.
VIII B. When space constraints and spatiotemporal dynamics are factored in, systems approaches become indispensable. A true understanding of the integration between endocytosis and signaling circuitries therefore requires systems biology. In this section, we review some of the most recent advances in the field of endocytosis from a systems perspective. We will cover two rather different, though complementary, approaches to the analysis of molecular networks.
The first, the top-down approach, addresses the property of large networks, generally obtained with high-throughput data. Such data are generally static and are analyzed with the tools of network biology Following a general trend, we will also include, in our discussion, papers reporting high-throughput data per se without network analysis. The second brand of systems biology, the bottom-up approach, deals with the analysis of much smaller networks generated by molecular biology and genetics techniques.
In this case, the approach involves the formulation of mathematical models and their numerical simulations. Endocytosis has been analyzed both via top-down and bottom-up approaches. In recent years, reviews have discussed the bottom-up approaches of systems biology in particular, see Refs. Here, we will present an overview of both approaches, with particular emphasis on results produced in recent years.
The analysis of the CME interactome was one of the first examples of network analysis applied to an endocytic pathway ; see also Ref. The CME network analysis draws on the extensive amount of biochemical, structural, and proteomic data relating to CME and collected over the last 20 years or so reviewed in Refs. These studies were integrated with RNA interference screenings that provided a functional characterization of this pathway , , , , In addition, the advent of mass spectrometry coupled to organelle purification has recently produced a large amount of quantitative data see, for instance, Refs.
RNAi-based screening and mass spectrometry studies were also recently applied to identify components of various NCE pathways , , One characteristic of the network is its modularity: small modules can be plugged-in and accommodated at the level of hubs still using the same overall network. This is the case for alternative cargo adaptors that are added to the network by binding to the AP-2 and clathrin hubs for the internalization of specific cargoes see below and sect.
Importantly, the interactions are frequently of low affinity, and multiple interactions ensure avidity, thus stabilizing the network , This gives rise to a dynamic instability of the network, and a certain number of interactions are required to allow network assembly and pathway progression.
Importantly, many of the accessory factors interact with AP-2 and clathrin in a mutually exclusive manner. Indeed, biochemical experiments revealed that the clathrin hub displaces the AP-2 hub, ensuring the timing and directionality of the process It is therefore crucial that network analysis takes into account the dynamic nature of the pathway, where at each step there are significant changes in the interactome picture Modularity of the pathway also emerges by looking at the conservation of the CME network: hubs are conserved across species, while other nodes are sometimes lost in species distant to mammals.
In addition, clathrin and AP-2 have maintained their specialized functions across evolution: a non-self-polymerizing cargo recognition module AP-2 , and a cage-forming module clathrin. This allows flexibility in cargo repertoire and ensures in-built fidelity. Dynamin forms another important hub. In this case, the connectivity relying on this protein might have even more far-reaching implications for cell physiology. Dynamins intersect a variety of pathways. However, it is also crucial for actin dynamics reviewed in Ref.
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VII B , directed cell migration sect. VII B , centrosome cohesion at mitosis sect. VIID , cytokinesis sect. VII D , and apoptosis not reviewed here, but see Refs. Thus the interconnectivity exerted by the dynamin hub might reflect a higher level of integration among different or perhaps only apparently different, see sect. X territories of cellular regulation. Another interesting example of network analysis applied to a proteomic screening is provided by the recently obtained EGF-regulated UB proteome This study revealed that in addition to well-established liaisons with endocytosis-related pathways, the EGF-Ubiproteome intersects many circuitries of intracellular signaling involved in DNA damage checkpoint regulation, cell-to-cell adhesion mechanisms, and actin remodeling.
One very important implication of network analysis that is potentially relevant to the design of new therapies for human diseases is that, in addition to acting as critical interconnections between signaling pathways, hubs are also points of fragility of signaling networks As such, they represent ideal targets for pharmacological intervention.
An interesting example in this sense is the depletion of the AP-2 hub, which affects CME to different extents, depending on the type of cargo , , , A siRNA screening study for genes involved in endocytosis in C. A similar approach was taken by Zerial and colleagues who developed a siRNA screening for identifying genes involved in endocytosis, and also their contribution to 10 specific phenotypes of endocytosis which were rigorously quantified number of endosomes, distance from the nucleus, size of endosomes, etc.
This group used a quantitative multiparametric image analysis approach to assess the variation of the 10 selected phenotypes in cells treated with both EGF and TF for 10 min. Their study showed that cells can adjust endosome size, number, and location distance from the nucleus. The study also demonstrated that genes regulating EGF endocytosis, and thus cargo uptake, were different from those involved in TF endocytosis, and thus in cargo recycling. Finally, they confirmed a strong feedback between endocytosis and signal transduction pathways. To be understood at the mechanistic level, these high-throughput data need to be integrated into mathematical models of signaling, which we will briefly review in the next section.
We shall see that the gap between these two approaches has been narrowed, as high-throughput data have become more quantitative and as models have started to keep track of both spatial and time resolved signaling cues. Endocytosis has been described in mathematical models of two specific subjects: 1 signal transduction pathways and 2 the formation of polarized structures during asymmetric cell division. While the role of endocytosis in setting the timing of the different events has always been thoroughly investigated, the spatial dimension, that is more difficult to address mathematically, has received less attention.
Models of signal transduction pathways were produced well before the term systems biology was coined. These were among the first of only a handful of successful models coupled to experimental results that led to new ideas and experimental tools, such as the endocytic rate constant, a measure that is still widely used by experimental biologists to quantify internalization , Over the years, new molecular details have been introduced into signal transduction pathway models, particularly for EGF signaling, to produce some of the most detailed models developed by systems biologists so far, involving a large number of reactions and molecular players, and generally described by ordinary differential equations 73 , , These models primarily focus on the timing of signal transduction pathways.
Both the dynamics of endomembranes and endocytosis, though, are well described by specific models devoted to their particular analysis. The original model of Heinrich and Rapoport that describes the vesicular transport system was updated by more recent models that have addressed the transition from early to late endosomes. This process involves the so-called RAB conversion, whereby early endosomes, carrying a high density of the small GTPase RAB5, are irreversibly transformed into late endosomes, with RAB7 being the prevailing species see sect. IV A2. The presence of a positive-feedback loop in the interaction between RAB5 and its guanine nucleotide exchange factor GEF RABEX-5 has been identified as an important source of nonlinearity that underlies the switch.
The positive-feedback loop guarantees the enrichment of RAB5 in the early endosomes and needs to be inactivated during the conversion to late, RAB7-enriched, endosomes. Figure 5. Positive-feedback loops playing a role in systems level properties related to endocytosis. B : positive-feedback loops have also been invoked to explain the mechanical process of endocytosis.
The model, originally developed for yeast, applies in general to eukaryotes. As actin remodeling leads to PM invagination, a first positive-feedback loop is created by BAR domain-containing proteins RVS in yeast, shown as BDPs-BAR domain proteins, in the figure , which envelop the membrane, creating a curvature that further helps BDP binding to the tubular structure that has formed.
The presence of BDPs protects part of the membrane from the activity of a PIP 2 phosphatase PPase , which can act on the free part of the invagination i. A second positive-feedback loop has been proposed whereby the effect of PIP 2 depletion from the bud increases the curvature at the interface between the bud and the tubule covered by BDPs, and PPase activity is further reinforced by this increase in curvature not shown. As a result, the bud is eventually pinched off.
C : during bud formation in budding yeast, CDC42 accumulates at the bud site. The asymmetric distribution of the protein has been proposed to be driven by two overlapping positive-feedback loops. In the first, slower, loop, the localization of CDC42 favors the accumulation of actin filaments, which in turn deliver more CDC42 to the site. Free diffusion on the membrane and endocytosis allow the redistribution of CDC42 away from the bud-site, while active transport along actin filament reverses this process. As for endocytosis itself, a recent biophysical model of endocytosis in yeast has stressed the importance of the interplay between chemical reactions and mechanical deformations of the PM , The model is based on data describing the recruitment of different molecular players to the PM before and during endocytosis.
This time, the loops are based on the interaction between enzymes that control pulling forces and pinching of the membranes, and the resulting membrane curvature that enhances the activity of the enzymes. Along these lines, a recent study in mammalian cells supports the model with respect to the generation of PIP 2 -depleted domains on the PM, created through the coupling of specific phosphatases with molecular machinery capable of sensing membrane curvature ; see also sect.
III A3. The dependency of signaling on space and time has been modeled by the group of Boris Kholodenko who pioneered the study of the role of spatial gradients in signaling Their results showed how in the presence of constant inactivating signals distributed all over the cytoplasm, a very steep gradient of signals would form if signal transduction pathways were to deliver their signal simply by free diffusion.
Using sensible parameters for diffusion coefficients, they demonstrated that in some instances it is the signaling endosomal compartments that permit the signal to pass through this cytoplasmic inactivating barrier for delivery to the nucleus A further step towards the integration of time, space, and signaling see Refs.
The most thorough analysis produced so far addresses the activation of H- and N-RAS which we will refer to globally as RAS following growth factor treatment , whose presence activates a signal differentiated both in time and in space: while RAS activation at the PM is fast and quickly disappears, signaling continues for a longer time from the Golgi. With a combination of models and single-cell live cell measurements, it was shown that two overlapping dynamics contribute to guarantee the spatial-temporal dynamics of RAS activity after growth factor treatment in MDCK cells. The first is the so-called acylation cycle, which controls RAS localization.
Ubiquitous depalmitoylation decreases the affinity of RAS for endomembranes, thus increasing its diffusion rate, while repalmitoylation, operated at the Golgi, stabilizes RAS in this compartment. In this way, RAS localizes preferentially to the Golgi, from which it is sent back to the PM via the secretory pathway. Arguably, systems biologists working from a bottom-up perspective on endocytosis will have to introduce space as a fundamental component of their models to further understand the intricate connection between endocytosis and signaling.
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Along this line, it will be possible to make use of the data obtained by the high-throughput studies of endocytosis described above Cell polarization is a field that requires the contribution of endocytosis to be necessarily described both in space and time. Saccharomyces cerevisiae has successfully been used for the development of models to analyze the establishment and maintenance of polarity in cells.
In particular, the process of bud formation, typical of yeast, has been analyzed with systems biology approaches that have underlined the role of endocytosis in creating one single focus of budding precursors on the PM. A proposed model suggests that the symmetry breaking, taking place during bud development, is triggered by a positive-feedback loop whereby CDC42, a small RHO GTPase required for budding, favors the positioning of actin cables which in turn contribute to cluster CDC42 on the membrane In this sense, the interplay between endocytosis and delivery to the PM via actin cables, to generate a spatially uneven distribution of CDC42, resembles the above-mentioned acylation cycle of RAS.
This result has been challenged by stochastic models that explicitly include vesicle fluxes by endocytosis and exocytosis at the PM. Conversely, loosely associated membrane transducers, including CDC42, have much faster diffusion rates that, coupled with actin-directed vesicle traffic, are predicted to hinder, rather than to reinforce, polarization in yeast One of these components may be represented by molecules, such as septin, that set a diffusion barrier on the plasma membrane, thereby limiting lateral diffusion of CDC42 along the cell cortex.
Consistently, septins, which are small GTPases enriched at the bud site of a dividing yeast reviewed in Ref.
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In the daughter cell, this event is necessary to maintain CDC42 polarized localization, which may be initiated by directed exocytic vesicle delivery. Thus a synergic action between membrane trafficking and septins may operate to maintain the dynamic polarization of CDC42 during asymmetric growth in yeast. In this section, we tackle the issue of how endocytosis and signaling are integrated during the execution of complex biological programs. From what we have reviewed so far, it should be evident that all proliferative, differentiative, apoptotic, metabolic, and developmental cellular programs controlled by membrane receptors are also governed by endocytosis.
We do not dwell, therefore, on biological aspects that are evident consequences of endocytic control over signaling at the circuitry level; rather, we try to provide an account of biological programs in which the impact of endocytosis is or was less obvious and more complex. We will start by reviewing knowledge on an endocytic organelle, the caveola, whose study is unveiling surprising overlapping levels of complexity in the interconnection between endocytosis and signaling.
We then move to the description of cellular programs in which the impact of endocytosis is paramount, i. Caveolae are small 60—80 nm in diameter , flask-shaped, invaginations of the PM. Despite having been first observed more than half a century ago , their function is still the object of intense investigation and debate. They have been implicated in NCE, cell adhesion, signal transduction, redox signaling, lipid and cholesterol regulation, mechanosensing, and possibly even in the regulation of transcription. Caveolae are enriched in certain sphingolipids, cholesterol, and PIP 2 , , , They represent therefore a subset of membrane lipid rafts.
Caveolae are associated with microtubules , and with the actin cytoskeleton, this latter connection possibly being mediated by filamin Two families of protein components are crucial structural and regulatory components of caveolae: caveolins caveolin-1 through -3 and cavins cavin-1 through The relevance of caveolins to the biogenesis of caveolae was established through the genetic disruption of caveolin-1 gene, which resulted in mice lacking caveolae , and by overexpression of caveolin-1 in caveolae-deficient cells, which resulted in caveolae formation The interaction between caveolin-1 and cholesterol is critical for the oligomerization of the former , and this is probably important for the ability of caveolin to influence membrane curvature by inducing or stabilizing it , , The exact structural role of caveolins in the formation of caveolae is still the object of investigation and debate see Refs.
In addition to caveolins, four cavins are also critical for the formation of caveolae at the PM 49 , , , , Cavins form a multiprotein complex that is recruited by caveolin-1 to the PM, in a cavindependent manner 49 , where it stabilizes caveolae. Interestingly, cavin-1 does not associate with other pools of caveolin-1 for instance, that present in the Golgi, Refs. In this contention, it is of note that cavins bind to phosphatidylserine in vitro and that caveolins might generate phosphatidylserine-enriched domains at the PM While the interested reader will find a wealth of additional information on cavins in recent reviews 50 , , it is of interest that cavin-1 was originally identified as a transcription termination factor, named PTRF polymerase I and transcript release factor, Ref.
Caveolae have been implicated in the endocytosis of several ligands, including integrins, glycosphingolipids, and certain viruses, such as polyoma and SV40 reviewed in Refs. Caveolar endocytosis might be tightly linked to the process of cell adhesion, as supported by findings that, in the case of caveolae-mediated SV40 internalization , , several kinases regulating the process are also involved in cell adhesion In addition, integrin activation might regulate caveolar endocytosis, and in turn, caveolar internalization might remove integrins from the cell surface, suggesting bidirectional communication between the two processes True enough, evidence supporting opposite contentions, stimulation versus inhibition of caveolar endocytosis by integrins, has been provided , , reviewed in Ref.
VII B2 for a specific example ; however, while differences need to be resolved, the concept of connection between caveolae and adhesion seems established. It should also be said that the exact endocytic function of caveolae remains the object of debate in the field. First, many proteins that enter the cell through caveolae might also be internalized through different portals. Second, caveolae are by-and-large relatively immobile and stable structures at the PM , , ; but see also below for a recent revisitation of this concept , and also caveolins and cavins are remarkably long-lived proteins undergoing very slow turn over , Indeed, caveolin-1 has even been proposed to function as a negative regulator of caveolae endocytosis, by slowing down their turnover and stabilizing them at the PM Finally, even SV40, a traditional caveolar cargo, was recently also found in noncaveolar vesicles , and it was shown to be internalized with faster kinetics in caveolinnull cells A stimulating account of the debate on the endocytic function of caveolae can be found in Reference While the above evidence does not deny the endocytic nature of caveolae, it draws attention to the facts that 1 probably not all internalization events thought to be executed through caveolae are really as such, and 2 even bona fide caveolar internalization events must be stringently regulated to account for the rather nondynamic nature of these organelles.
A recent study unveils the regulation at the basis of caveolae and caveolin-1 assembly, disassembly, and degradation Indeed, by altering the balance of core caveolae components caveolin-1, cavins, and cholesterol , it is possible to accelerate caveolin turnover, by inducing caveolae disassembly, and caveolin ubiquitination and degradation into the lysosome It was proposed that this process might be involved in the normal life cycle of caveolae: trafficking to early endosomes following internalization might cause the disassembly of the caveolar scaffold due to cavin loss, followed by caveolin-1 degradation In this contention, a recent paper unveils a more dynamic nature of caveolae than previously thought By monitoring caveolae for long periods of time, it was found, however, that the vast majority of caveolae are dynamic with lifetimes ranging from a few seconds to several minutes.
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Thus probably two pools of caveolae exist: a short-lived and a long-lived one Interestingly, the dynamics of caveolae are affected during mitosis, when the arrival and departure of caveolae, at the PM, becomes skewed towards the latter, causing a redistribution of caveolin-1 from the PM to intracellular compartments: an observation that adds to the involvement of endocytic dynamics in mitosis see sect. VII D , although its exact role remains to be determined Caveolae have also traditionally been regarded as assembly platforms for signal transduction machinery. This property has been largely ascribed to the protein-protein interaction abilities of caveolin-1, which can act as a scaffold for a surprisingly large number of signaling proteins, such as growth factor receptors and their downstream transducers, SRC-like tyrosine kinases, G proteins, GTPases, GPCRs, steroid hormone receptors, and the endothelial nitric oxide synthase eNOS reviewed in Ref.
While not all of these interactions are validated at a high level of resolution and functional certainty, together they define the idea that caveolin-1, and, by association, caveolae, function as a platform to regulate signaling. New developments in the field, however, compel some reevaluation of these findings.
It is clear now that caveolins are expressed in cells that do not show caveolae, such as neurons, in which they control signaling by neurotrophins and synaptogenesis, or leukocytes, where they exert control over inflammatory responses and T-cell activation reviewed in Ref.