Endocytosis and signaling: cell logistics shape the eukaryotic cell plan - PubMed (original) (raw)
Review
Endocytosis and signaling: cell logistics shape the eukaryotic cell plan
Sara Sigismund et al. Physiol Rev. 2012 Jan.
Abstract
Our understanding of endocytosis has evolved remarkably in little more than a decade. This is the result not only of advances in our knowledge of its molecular and biological workings, but also of a true paradigm shift in our understanding of what really constitutes endocytosis and of its role in homeostasis. Although endocytosis was initially discovered and studied as a relatively simple process to transport molecules across the plasma membrane, it was subsequently found to be inextricably linked with almost all aspects of cellular signaling. This led to the notion that endocytosis is actually the master organizer of cellular signaling, providing the cell with understandable messages that have been resolved in space and time. In essence, endocytosis provides the communications and supply routes (the logistics) of the cell. Although this may seem revolutionary, it is still likely to be only a small part of the entire story. A wealth of new evidence is uncovering the surprisingly pervasive nature of endocytosis in essentially all aspects of cellular regulation. In addition, many newly discovered functions of endocytic proteins are not immediately interpretable within the classical view of endocytosis. A possible framework, to rationalize all this new knowledge, requires us to "upgrade" our vision of endocytosis. By combining the analysis of biochemical, biological, and evolutionary evidence, we propose herein that endocytosis constitutes one of the major enabling conditions that in the history of life permitted the development of a higher level of organization, leading to the actuation of the eukaryotic cell plan.
Conflict of interest statement
Disclosures
No conflicts of interest, financial or otherwise, are declared by the authors.
Figures
Figure 1
Endocytosis controls signaling. Examples are provided of how endocytosis and recycling control signaling at different levels and cellular locations. References to the depicted circuitries (in this and all subsequent figures) are in the main text. A: endocytosis regulates signaling at the PM. Endocytosis extinguishes signals by routing PM receptors to degradation. In addition, even in the presence of continuous endosomal signaling (see below), endocytosis extinguishes signals dependent on the assembly and activation of molecular transducers exclusively localized at the PM, by removing receptors from the PM. Two examples are provided. In the case of RTKs (exemplified by EGFR, a), ligand binding and receptor autophosphorylation allow binding to SH2-domain containing lipid kinases (e.g., PI3K) or lipases (e.g., PLC-γ), which mediate RTK-dependent signaling by using PM-enriched phospholipids as substrates. Endocytosis of the RTK, therefore, extinguishes this type of PM-restricted signaling. In the case of GPCR signaling (b), ligand binding permits the coupling with heterotrimeric G proteins (α and βγ). This allows GPCR to act as GEFs for G_α_, a step necessary for the ability of G_α_ to activate adenylyl cyclase and signaling. Since heterotrimeric G proteins are PM-resident (with some notable exceptions, as depicted in panel C-i), the internalization of the GPCR [which can proceed through ARR-independent (b) or ARR-dependent (c) mechanisms] extinguishes the PM-based signal. Furthermore, upon ligand binding, GPCRs can become phosphorylated (c) and bind to ARR, which prevents the recruitment of stimulatory G proteins (desensitization) and promotes CME, thus terminating signaling (c). Internalized ligand-GPCR complexes are routed to early endosomes, where the reduced pH causes the dissociation of the ligands from their receptors, as well as receptor dephosphorylation by an endosomally localized PP2A phosphatase (d). The subsequent rapid recycling of receptors to the PM allows the reexposure of resensitized GPCRs at the cell surface (d). Ligand availability is also controlled by endocytosis. For example, in NOTCH signaling, endocytosis and recycling of DELTA to restricted regions of the PM may promote high local levels of ligand, thus causing robust NOTCH activation (e). Additionally, posttranslational modifications, such as monoubiquitination, of DSL ligands in the recycling compartments might also activate the ligands, via as yet ill-defined mechanisms (e). B: different endocytic routes modulate signal duration. Several receptors can be internalized through both CME and NCE, and the relative partitioning of receptors between the two entry routes determines the final biological output. For EGFR and TGF-β_R, CME (red arrows) and NCE (black arrows), respectively, destine receptors preferentially to recycling to the PM (f) or degradation (g). Recycling leads to sustained signaling, while routing to lysosomes terminates signaling. Other cargoes exploit the two internalization pathways in the opposite manner (not shown). C: endosomes act as signaling platforms. The signaling endosome hypothesis was originally proposed in neurons where endosomes were postulated to serve as platforms for the assembly and transport of protein complexes for long-range signal transmission. Several neuronal and nonneuronal receptors exploit the unique physical-chemical properties of endosomal membranes to either prolong signals originating from the PM, or to specify and diversify signaling outcome. A paradigmatic example is provided by sustained endosomal activation of ERK kinases. Endosomes are enriched in specific adaptor proteins, such as P18 that serves as an anchor for an ERK-activating scaffold (MEK1/MP1/P14). This allows ERK signaling from the endosome upon activation of EGFR, in addition to PM-originated ERK signaling (h). A similar situation occurs for signaling along the GPCR-ARR-ERK axis (not shown). In this case, endosomes act as platforms that, in addition to prolonging ERK signaling, also bias it towards predominantly cytosolic rather than nuclear ERK substrates. In the case of the GPCR PHTR, different conformations of the receptor, associated with the binding to PTH or PTHrP, lead to different signals (i). The PTHrP:PTHR complex signals canonically from the PM. Conversely, PTH stimulates cotrafficking into early endosomes of PTHR with stimulatory G_α that promotes adenylyl cyclase (A cycl.) activation and production of cAMP from that location (i). Endosomes can also act as intermediate stations for the propagation of signals to the nucleus. Activation of EGFR stimulates the translocation of APPL1 from endomembranes to the nucleus, where it controls the activity of chromatin remodeling enzymes (not shown). Similarly, HGF stimulation of MET receptor promotes STAT3 activation both at the PM (j) and on endosomes (k). STAT3 must translocate to the nucleus to promote transcription. When MET activation is weak, such as in the presence of limited amounts of ligand, endosomes are used to transport STAT3 to the nucleus, while protecting it from being deactivated by cytosolic phosphatases (k). Finally, there is increasing evidence of endosome-directed signal specificity. This is the case for SARA-endosomes mediating TGF-_β_R signaling. The recruitment of SMAD2 by SARA leads to phosphorylation of SMAD2 by internalized TGF-_β_R. Phosphorylated SMAD2 dissociates from the receptor and forms a complex with SMAD4 that translocates to the nucleus, where it regulates gene transcription (l).
Figure 2
Multiple and bidirectional connections between actin dynamics and endocytosis. A: endocytosis and recycling harness actin dynamics. Macropinocytosis, phagocytosis, and most forms of NCE are dependent on actin dynamics. The requirement for actin polymerization in CME in mammalian cells is less well established. However, recent evidence, mainly obtained using advanced live imaging, has shown that actin and actin regulatory proteins are invariably recruited along each of the various steps of CME and that they mediate key events in the transport and motility of endosomal vesicles. The initial curvature (a) of the PM is generated by the assembly of clathrin coats and additional endocytic proteins (not shown), such as F-BAR-containing membrane deforming proteins. As invagination proceeds (b), changes in curvature may be sensed by other BAR-domain-containing proteins that cooperate with the large GTPase dynamin (not shown) and actin polymerization regulatory factors to promote neck formation (c), which precedes vesicle scission (d). Proteins of the endocytic coat (not shown) may directly link the membrane to the actin network. Actin polymerization may generate the force necessary to promote pit invagination into the cell, until dynamin-mediated scission occurs. Alternatively, an actin shell that nucleates along the sides of invaginating membrane tubules may cause membrane reorganization, lipid domain repartition, and line tension, aiding dynamin-dependent scission. Actin is also involved in vesicle motility and trafficking inside the cells (d) and has recently been shown to influence cargo sorting (e). This is the case for _β_2ARs that generate endosomal, actin-coated, subdomains by recruiting actin regulatory factors through their PDZ-interacting motives. This provides a physical basis for sequence-dependent sorting of internalized membrane proteins from distinct domains within the same endosome, enabling separation and diversification between bulk [here, represented by TFR recycling (f)] and sequence-dependent (_β_2AR), actin-mediated recycling to the PM (e). Thus actin may be crucial not only for endosomal motility, but also for cargo-mediated regulation of receptor recycling. B: endocytosis and recycling control actin dynamics-based migration. Coordination between membrane traffic, cell substrate adhesion, and actin remodeling is required to generate and spatially confine the forces responsible for the formation of polarized cell protrusions, such as lamellipodia and circular dorsal ruffles (CDR). Two endocytic/signaling networks implicated in polarized migration are shown. In the first one (g–h), in response to stimulation of RTKs, such as HGF stimulation of the MET receptor, CME and RAB5 activation promote the internalization of RAC and its GEF, TIAM1, into early endosomes (g). Activated GTP-bound RAC is subsequently recycled through the ARF6 endosomal pathway (h) to confined PM regions, where actin polymerization supports the formation of CDR, a step that occurs prior to the extension of migratory protrusions. In the second network (n–o), the trafficking of integrins, through CME and raft-dependent NCE, enables sustained and polarized integrin signaling to lamellipodia as well as precise coordination of integrin activity with the changing dynamics of focal adhesions. Integrins, such as _α_5_β_1, are continuously internalized (i) and recycled to the PM, through RAB25-endosomes that are compartmentalized at the leading edge of cells for lamellipodial extension. Coordination of integrin adhesion and lipid raft endocytosis and recycling is also crucial to integrate RAC and integrin activation (j). Lipid rafts are endocytosed through caveolin-1 (CAV1)-containing caveolae (j). Lipid rafts are also binding sites for RAC (k). Integrin signaling blocks lipid raft internalization by promoting CAV1 phosphorylation and its retention in focal adhesions at the PM (l). Thus, when integrins are engaged by the ECM, RAC binding sites at the PM become available. On the contrary, cell detachment abrogates integrin activation and extinguishes RAC signaling at the PM, by enabling the relocalization and subsequent caveolae-mediated internalization of CAV1 and lipid rafts. Recycling of CAV1 (m), as well as of RAC (h) and integrins may be coordinated by ARF6. Mature, integrin-containing focal adhesions at the rear of the cells need to be disassembled to enable effective cell locomotion. This process involves dynamin and CME (n). Finally, internalized integrin, bound to ECM ligands such as fibronectin (FN), may be specifically directed to lysosomes for degradation, through a mechanism involving integrin ubiquitination and recognition by the ESCRT machinery (o). Cells expressing a ubiquitination-deficient _α_5_β_1-integrin mutant are impaired in cell migration, suggesting that FN-integrin complex turnover is essential for locomotion.
Figure 3
Transcriptional programs controlling endocytosis and genetic reprogramming by endocytosis. A: activation of HIF1_α_ during hypoxia causes the inhibition of the RABAPTIN-5 gene transcription and, consequently, endosomal retention of the EGFR, eventually leading to sustained EGFR signaling from the endosomal station and tumor progression. B: lysosomal stress causes nuclear translocation of the TFEB transcription factor, which induces transcription of a cluster of genes involved in lysosomal biogenesis. C: upon different types of cellular stresses, p53 translocates into the nucleus and activates the transcription of genes which play roles at different stations of the endocytic pathway: DRAM1, a lysosomal membrane protein; TSAP6 and CHMP4C, which are involved in exosome release from MVBs; CAV-1, which stimulates caveolar endocytosis. D: at the MVB, the ESCRT complex is assembled (CHMP4 being one of its components), which is involved in the recognition of ubiquitinated cargoes, and in invagination and scission of intraluminal vesicles (see sect. V_C_). Subunits of the ESCRT-II complex can selectively bind to mRNAs. MVBs are also platforms for the assembly of the RISC complex, which directs the degradation or translational repression of target mRNAs. In particular, two components of the RISC are specifically enriched at this site, AGO and GW182. All these events participate in the regulation of exosome secretion, which in turn is a tool for genetic reprogramming of adjacent cells. E: TP53 mutations found in human cancers exert part of their oncogenic potential through the P63-dependent (transcriptional-dependent) stimulation of RCP-mediated recycling of integrin-EGFR complexes, leading to induced migration and metastasis. The molecular mechanism for this remains unclear.
Figure 4
The ubiquitin system and endocytosis. A: EGFR (and MET, not shown) ubiquitination by CBL. A GRB2-CBL complex binds to the receptor through interactions of i) the SH2 domain of GRB2 with pY1068 or pY1086 of EGFR, and ii) the tyrosine kinase binding (TKB) domain of CBL (either c-CBL or CBL-b) with pY1045. a: EGFR-bound CBL becomes phosphorylated and activated. b: Recruitment of E2 (not shown) to the RING domain of CBL results in covalent attachment of monoUb and polyUb chains to the kinase domain of the receptor (c). B: AIP4 mediates ubiquitination of CXCR4. Upon agonist-mediated activation, CXCR4 becomes phosphorylated at Ser324 and Ser325 by an unknown kinase (d). This leads to the recruitment of the E3 ligase AIP4, through its WW domain (e), that ubiquitinates the receptor (f). C: ENaC ubiquitination by NEDD4–2. NEDD4–2 binds to ENaC PPxY motifs and catalyzes its ubiquitination (g). This induces ENaC endocytosis and lysosomal targeting, resulting in fewer channels at the cell surface (g). To increase Na+ transport, NEDD4–2 is phosphorylated by kinases, including PKA, SGK, and IKK_β_, in turn activated by various signaling pathways (h). Phosphorylation of NEDD4–2 induces binding of 14–3-3 dimers (not shown), which prevents NEDD4–2 from binding to ENaC. As a result, endocytosis of ENaC is inhibited (i), and increased ENaC presence at the surface enhances epithelial Na+ absorption. 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.g., the arginine transporter Can1) (j). Through their PPxY motifs, ARTs bind to the WW domain of Rsp5 (j) and mediate ubiquitination of cargo (k). 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. Agonists induce rapid ubiquitination of GPCR-recruited ARR by MDM2, a process required for receptor internalization. F: ubiquitination of adaptors by EGFR. Activated EGFR is ubiquitinated at the PM by CBL (A) and recruits UBD-containing endocytic proteins such as EPS15, epsin, and HRS (at the endosome). These adaptors, in turn, are ubiquitinated by NEDD4 through a process known as coupled monoubiquitination (cU).
Figure 5
Positive-feedback loops playing a role in systems level properties related to endocytosis. A: during the conversion from early (red) to late endosomes (blue), the GTPase RAB5 is replaced by RAB7. Two positive-feedback loops (shown as “+” in the figure) help the endosomes to maintain their enrichment in either of the two RABs. The first loop involves RAB5 and its GEF-complex (Rabaptin-5/RABEX-5), while the second involves RAB7 and the class C VPS/HOPS complex (GEF in the picture). To explain the switch from early to late endosomes, a negative-feedback loop has been hypothesized whereby RAB7 inhibits RAB5 (not shown) in the so-called “cut-out model.” According to this model, after RAB5 reaches a critical level, it triggers the RAB7 feedback loop, which leads to both an enrichment in RAB7 and to the silencing of the RAB5 enrichment loop. More recently, it was reported that SAND-1 is involved both in the recruitment of RAB7 to endosomes, and in the inhibition of RAB5 activity (likely through the inhibition of RABEX-5). Thus SAND-1 might be the molecular switch driving endosomal RAB conversion. 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 (RVS167 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 PIP2 phosphatase (PPase), which can act on the free part of the invagination (i.e., the bud). A second positive-feedback loop has been proposed whereby the effect of PIP2 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. In this model, the transition between active CDC42 (CDC42-GTP) and inactive CDC42 (CDC42-GDP) is not affected by the distribution of CDC42; thus, in the figure, we do not specify the species to which CDC42 is bound. D: in the second, faster, positive-feedback loop, the activation/inactivation of CDC42 plays a key role. GTP-bound CDC42 is stably localized at the PM, whereas GDP-bound CDC42 shuttles freely between PM and cytoplasm. The presence of a pool of active CDC42 (CDC42-GTP) triggers a positive-feedback loop because it recruits the scaffold protein BEM1 and the GEF CDC24 to the PM. At the PM, CDC24 causes the activation of more CDC42, which in turn recruits more BEM1:CDC24 complexes, thereby producing a positive-feedback loop in the activation of CDC42.
Figure 6
Endocytic circuitries in asymmetric cell division. A: ACDs in the Drosophila SOP lineage. The SOP lineage is shown. All divisions are asymmetric and entail directional (DELTA to NOTCH) signaling between daughter cells (depicted by red arrows). The first division (from SOP to pIIa and pIIb) is shown in detail. The plane of division with orientations is indicated. Asymmetrically partitioned molecular machinery (NUMB, AP-2, and SARA endosomes) is also shown. B: endocytosis regulates the creation of asymmetry in pIIa and pIIb cells. a: NOTCH is nonfunctional in pIIb cells, because it is internalized/degraded or because SANPODO is internalized. While the internalization of SANPODO is established, it is not clear whether NOTCH is actually preferentially/internalized degraded in the pIIb cell (indicated by a “?”). However, recent evidence in mammals indicates that NUMB might be an inhibitor of NOTCH recycling, rather than a positive modulator of internalization. Thus, in the pIIb cell, the function of NUMB may be to prevent NOTCH recycling to the PM, so favoring its degradation. b: DELTA-related events in pIIb. The E3 ligase Neuralized is asymmetrically partitioned in pIIb, allowing endocytosis of DELTA. DELTA is trafficked by epsin to a RAB11/SEC15-positive endosome (this event might be preceded by a first pass onto the PM to ”activate“ DELTA, see Figure 1_A_). These endosomes are then directed, for cargo release, along a branched ARP2/3-dependent actin network to a microvillar-dense region of the apical membrane of the pIIb. This region has been shown to contract extensive interactions with a similar region of the pIIa cell. c: DELTA-related events in pIIa. DELTA is also internalized in the pIIa cell through a Neuralized and UB-independent mechanism. In this cell, however, the recycling to the PM is blocked and DELTA is destined to degradation, because the RAB11-positive endosomal compartment cannot form, possibly because a critical RAB11 partner (Nuclear fallout/Arfophilin 1) is inactivated by as yet unclear mechanisms. DELTA might also be internalized before mitosis of the SOP cell; in pIIb, it could be recycled to the PM, whereas in pIIa it might be destined to a degradative pathway. d: Asymmetric partitioning of SARA-endosomes. In the SOP cell, both NOTCH and DELTA are trafficked to SARA endosomes before ACD. These endosomes are then directionally transported to the nascent pIIa cell, thereby contributing to asymmetry. The described events are not necessarily ”all or none“ situations. They might occur in both cells, with a cell-specific bias in favor of one of them that is further amplified through reinforcement/extinction events that lead from a quasi-symmetric situation to the final DELTA/NOTCH asymmetry needed for directional signaling (e).
Figure 7
Endocytic proteins in the control of cell division A: three phases of mitosis are represented in a temporal order (interphase, metaphase, and telophase). The internalization rate (red line) remains constant along the entire mitotic event. During interphase, internalization is balanced by high rate of recycling (green line). During metaphase, recycling decreases while internalization remains sustained. This leads to the accumulation of an intracellular pool of vesicles and endosomes, and to a reduction of the cell surface area. At telophase, recycling recovers and is polarized towards the midbody. In the blow up, the molecular details of polarized recycling towards the midbody are depicted. PI3P-enriched endosomes are recycled towards the midbody in a microtubule-dependent manner. Recycling is mediated by RAB11 (as depicted in the picture, but also by RAB35 and ARF6, not depicted for simplicity). SNAREs mediate fusion events at the cytokinetic furrow. PI3P is enriched at this latter site, and this permits the recruitment of FYVE-CENT (FYVE-C). FYVE-C binds to TTC19 and CHMP4B, a component of the ESCRT-III complex, to allow midbody constriction. B: a mitotic cell in metaphase is depicted. Chromatids (green) are aligned on the metaphase plate and are connected to spindle microtubules by kinetochores (red). At the cell poles, centrosomes are depicted in blue. As discussed in the main text, different endocytic proteins bind to some of these mitotic structures: dynamin, intersectin 2 (INT-2), and CDC42 bind to centrosomes; ARH binds to dynein at kinetochores and is involved in transport to centrosomes; RAB6A is recruited to kinetochores; and clathrin heavy chain (CHC) binds to spindle poles where it recruits TACC3, a substrate of the AURORA A kinase. In the bottom panels, a depiction is shown of the effects of depletion of various endocytic proteins on centrosomes and mitotic spindle organization: dynamin depletion causes centrosome separation, ARH-null fibroblasts have smaller centrosomes, ARR depletion causes centrosome duplication, INT-2/CDC42 depletion causes aberrant spindle orientation, and epsin-1-depleted cells show aberrant organization of the mitotic spindle. In the right panels, the effects are depicted of the depletion of various endocytic proteins on chromosome attachment and alignment: depletion of CHC causes chromosome misalignment, while RAB6 depletion causes detachment of the spindle microtubules from the kinetochores.
Figure 8
The endocytic machinery controls transcription. Examples of endocytic proteins shuttling in and out of the nucleus, thereby affecting gene expression, are shown. A: subunits of the ESCRT-II complex activate RNA polymerase II (Pol-II)-dependent transcription. B: APPL1/2 and ESCRT-III components bind to chromatin remodeling complexes. C: HIP1 and the ESCRT-I component TSG101 bind to two known transcription factors (TFs), the androgen receptor (AR) and the glucocorticoid receptor (GR), respectively, to transactivate transcription at their sites (ARE, androgen responsive element; GRE, glucocorticoid responsive element). TSG101 can also either activate or inhibit AR transcription, through different mechanisms depending on the cellular context. D: ARR transactivates transcription either by binding to promoters directly or by binding to p300 histone deacetylase. Additional endocytic proteins depicted in the picture (EPS15, EPS15R, epsin, CALM, and clathrin) shuttle into the nucleus and affect transcription either by binding to TFs or to chromatin remodeling complexes (not depicted for simplicity). Endocytosis also delivers cargo to the inner nuclear membrane, by way of a retrograde transport mechanism. Two examples are shown. In the first, two membrane-anchored growth factors, pro-AR (precursor of amphiregulin) and pro-HB-EGF (precursor of the heparin-binding EGF-like factor), are delivered in a signaling-dependent and endocytosis-dependent manner to the inner nuclear membrane, where they sequester transcriptional repressors (E, in the case of pro-HB-EGF) or function as chromatin-remodeling agents (F, in the case of pro-AREG). In the second, the EGFR (G) is retro-transported via endocytosis in a complex with Importin β, which facilitates its translocation through the nuclear pore complex and its delivery to the inner nuclear membrane. Here, the receptor interacts with the translocon SEC61_β_, which catalyzes its membrane extraction and delivery to the nucleoplasm, where it activates transcription (G), either by direct binding to promoters or by binding to TFs. Finally, TP53 is controlled by the endocytic protein NUMB. NUMB inhibits the ubiquitination of TP53 by MDM2, thereby preventing its degradation, leading to increased TP53 levels and increased p53 transcriptional activity (H). Because the MDM2:NUMB complex shuttles in and out of the nucleus, it is not clear whether the regulation of TP53 by NUMB occurs in the cytosol or in the nucleus. In the mammary stem cell compartment (I), NUMB partitions into the daughter cell that adopts the stem-cell fate. One intriguing possibility is that this might drive high levels of TP53 in the daughter stem cell and its withdrawal into quiescence.
Figure 9
Endocytic genes in Mendelian (monogenic) diseases and in cancer. A: endocytic genes and Mendelian diseases. A list of 339 genes, including 277 genes encoding proteins involved in endocytosis and traffic and 62 proteins involved in regulation of the actin cytoskeleton, was used to screen the OMIM and GENE databases (see Table 2 for details) for their mutations in Mendelian diseases. Of these genes, 289 were present in OMIM, and 72 were listed as the cause of at least one disease (the complete list is in Table 2), indicating a frequency of mutation of 24.9% (red bar). This value was compared with the frequency of Mendelian disease genes among all human genes. An upper and lower limit for this frequency is shown (blue bars), calculated as detailed in the main text. Significance of the enrichments was tested by hypergeometric tests. The P values were obtained using the phyper function from the R statistical language (
). B: endocytic genes are enriched in ”old genes.“ Data relative to the phylogenetic age of all genes were downloaded from the Phylopat Database (
). The three age groups (old, middle, young) were defined as from Cai et al_._ (95). The relative distribution in the three age groups of all human genes (blue bars) and of the endocytic genes (red bars) is shown. P values were calculated with chi-square test. C: mutations of endocytic genes in the COSMIC database. Of the 339 genes (described in A), 160 harbored at least one mutation in at least one type of cancer. On the top of each bar, the number of genes harboring the number of mutations indicated on the _x_-axis is shown. For the ”frequently mutated” genes (>5 total mutations), the gene symbol is also shown (details are in Table 4). D: mutations of CBL in cancer and Mendelian diseases. In the middle of the panel, a schematic of the CBL protein is shown with its functional domains (TKB, tyrosine kinase binding domain; LR, linker region; RF, ring-finger domain; UBA, UB-binding domain). The ruler underneath shows amino acid positions. On the top, the position and the frequency of the mutations detected in myeloproliferative diseases are shown by solid circles, aligned with the amino acid sequence. At the bottom, the position of the mutations detected in NSCLC and in the Noonan-like syndrome is shown by red and green arrows, respectively. In NSCLC, the mutation at position 391 was detected in two tumors (shown as x2). In the Mendelian syndrome, four of five mutations affect the same resides (371, 367, 382, 420) as in myeloproliferative diseases.
Figure 10
The endocytic matrix. A conceptual drawing of the endocytic matrix is displayed. Starting from the primordial functions of endocytosis (green), connected with competition for food, a series of additional functions (yellow) became associated with the endomembrane system during evolution. These functions (yellow) were the consequence of 1) emerging properties of the system, such as size of endosomes, physical separation of signaling compartments (PM and endosomes), and origin of the nuclear envelope from endomembranes (see sect. IX_B_ and X_A_); 2) early convergence of endocytosis with other cellular functions and subsequent coevolution, as in the case of actin cytoskeleton and of the ubiquitination system (see sects. IX_A_ and X_A_); and 3) late convergence of endocytosis with other systems, such as pY-based signaling and the PAR complex (see sect. X, A and B). The consequence of these events is the pervasive presence of endocytosis and trafficking in virtually every cellular aspect of cell regulation (blue), and in the control of several cellular phenotypes (purple). The molecular (blue) and biological (purple) characteristics of this control are described in detail in the main text, with the exception of the role of endocytosis in neurotransmission, in particular at the synapse, which is not herein reviewed (for reviews on this issue, see Refs. 371, 720, 760).
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