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Keywords:

  • endocytosis;
  • lipid rafts;
  • receptor trafficking;
  • recycling;
  • receptor tyrosine kinase;
  • signal transduction

Abstract

  1. Top of page
  2. Abstract
  3. Endocytosis and endosomal targeting
  4. RTK signaling: plasma membrane versus endosome
  5. Internalization and retrograde signaling
  6. Degradation versus recycling
  7. Lipid rafts
  8. Conclusions
  9. Acknowledgements
  10. References

The trafficking of receptor tyrosine kinases (RTKs) to distinct subcellular locations is essential for the specificity and fidelity of signal transduction and biological responses. This is particularly important in the PNS and CNS in which RTKs mediate key events in the development and maintenance of neurons and glia through a wide range of neural processes, including survival, proliferation, differentiation, neurite outgrowth, and synaptogenesis. The mechanisms that regulate the targeting of RTKs to their subcellular destinations for appropriate signal transduction, however, are still elusive. In this review, we discuss evidence for the spatial organization of signaling machinery into distinct subcellular compartments, as well as the role for ligand specificity, receptor sorting signals, and lipid raft microdomains in RTK targeting and the resultant cellular responses in neural cells.

Abbreviations used
BDNF

brain-derived neurotrophic factor

EGF

epidermal growth factor

EGFR

epidermal growth factor receptor

ERK

extracellular-regulated kinase

FGF

fibroblast growth factor

FGFR

fibroblast growth factor receptor

GIPC

GAIP-interacting protein, C-terminus

Hrs

hepatocyte growth factor-regulated tyrosine kinase substrate

IGF-IR

type-I insulin-like growth factor receptor

IR

insulin receptor

MAPK

mitogen-activated protein kinas

MβCD

methyl-β-cyclodextrin

NGF

nerve growth factor

NRG

neuregulin

OL

oligodendrocyte

p75NTR

p75 neurotrophin receptor

PDGFR

platelet-derived growth factor receptor

PI-3K

phosphotidylinositol-3-kinase

PKC

protein kinase C

RTK

receptor tyrosine kinase

TGF

transforming growth factor

Trk

tyrosine receptor kinases

xGIPC

Xenopus homolog of mammalian of GIPC

Receptor tyrosine kinases (RTKs) belong to a broad family of transmembrane receptors that possess intrinsic kinase activity. RTKs are essential for development and maintenance of the PNS and CNS and regulate diverse neural processes, including cell survival, proliferation, differentiation, neurite outgrowth, and synaptogenesis (Weiner 1995; Huang and Reichardt 2003; Reuss and von Bohlen und Halbach 2003; Luikart and Parada 2006; Xian et al. 2007) (Table 1).

Table 1.   RTK essential functions in the nervous system
ReceptorNeural phenotype
  1. Overview of loss of function phenotypes for RTKs relevant to this review. IGF-IR, type-I insulin-like growth factor receptor; OPC, oligodendrocyte progenitor cell; RTK, receptor tyrosine kinase; OL, oligodendrocyte; EGFR, epidermal growth factor receptor; PDGFR, platelet-derived growth factor receptor; FGFR, fibroblast growth factor receptor; p75NTR, p75 neurotrophin receptor; Trk, tyrosine receptor kinases.

IGF-IROL development and myelination (Mason et al. 2003; Zeger et al. 2007); Neuronal development (Schlueter et al. 2007)
ErbB4OL maturation, myelin formation, dopaminergic function (Sussman et al. 2005; Roy et al. 2007); Neural crest and neuroblast migration, differentiation of olfactory interneurons (Tidcombe et al. 2003; Anton et al. 2004); Glutamatergic synapse function (Li et al. 2007); Repression of astrogenesis (Sardi et al. 2006)
EGFR (ErbB1)Survival of neurons in the frontal cortex, olfactory bulb, and thalamus. Survival and proliferation of cortical astrocytes (Sibilia et al. 1998; Wagner et al. 2006); Astrocyte development and neuronal survival (Kornblum et al. 1998); Oligodendrogenesis and remyelination (Aguirre et al. 2007)
PDGFR-αNumber of OLs, proliferation of OPCs (Murtie et al. 2005)
PDGFR-βInhibition of AMPA excitatory input (Ohi et al. 2007); Protection of neurons from glutamate-induced toxicity (Ishii et al. 2006)
FGFR3Proliferation and apoptosis of cortical progenitors (Inglis-Broadgate et al. 2005; Thomson et al. 2007); axonal development (Jungnickel et al. 2004); OL differentiation (Oh et al. 2003)
FGFR1Regulation of neural tube development (Deng et al. 1997; Hasegawa et al. 2004); OL differentiation (Zhou et al. 2006)
p75NTRNegative regulation of hippocampal pyramidal neuron dendritic morphology and neurite outgrowth (Zagrebelsky et al. 2005); Schwann cell migration, remyelination (Bentley and Lee 2000; Song et al. 2006; Tomita et al. 2007)
TrkADevelopment of sensory sympathetic and cholinergic neurons (Smeyne et al. 1994; Fagan et al. 1996)
TrkBDevelopment of motor and/or sensory neurons (Ernfors et al. 1994; Klein 1994; Pinon et al. 1996); Interneuron migration (Polleux et al. 2002)
TrkCDevelopment of sensory neurons (Klein et al. 1994; Liebl et al. 1997)

Activation of RTKs by their cognate growth factor or polypeptide ligands results in the autophosphorylation of specific tyrosine residues within the C-terminal tyrosine kinase domain of the receptor. This leads to receptor interactions with Src homology-2 domain containing adaptor and signaling proteins (Pawson et al. 2001) and the activation of downstream signaling pathways, including the mitogen-activated protein (MAP) kinases p38 and extracellular-regulated kinase (ERK1/2), phosphotidylinositol-3-kinase (PI-3K)/Akt, and phospholipase-C-γ pathways (Kaplan and Miller 2000; Hubbard and Miller 2007). Activated RTKs subsequently can be internalized through clathrin-coated pits, which pinch off from the plasma membrane and form clathrin-coated vesicles. Whereas many RTKs are internalized through a clathrin-dependent mechanism, clathrin-independent mechanisms, including internalization via macropinocytosis and lipid rafts/caveolae also have been described (Kirkham and Parton 2005; Valdez et al. 2007). Interestingly, and of relevance to this review, the internalization of RTKs through clathrin-dependent or -independent pathways has been linked to specific subcellular targeting and signal transduction in various cell types, including primary neuronal cultures (Di Guglielmo et al. 2003; Hibbert et al. 2006; Valdez et al. 2007).

Trafficking of RTKs and the concomitant activation of distinct signaling pathways is correlated with specific biological responses (Wiley and Burke 2001). However, the mechanisms that target RTKs to specific subcellular locations to initiate their diverse actions are not yet clear. In what follows, we discuss evidence for the spatial organization of signaling machinery into distinct subcellular compartments, as well as the role for ligand specificity, receptor sorting signals, and lipid raft microdomains in the targeting of RTKs and resultant cellular responses. Many of the studies that provide the basis for these data were performed in non-neural cells. Thus, we review some of this work as the basis for our general understanding of RTK trafficking and signaling but emphasize studies on RTK trafficking in neural cells, including studies on the neurotrophin tyrosine receptor kinases (Trks), p75 neurotrophin receptor (p75NTR), ErbB receptors including the epidermal growth factor receptor (EGFR/ErbB1), platelet-derived growth factor receptors (PDGFR), fibroblast growth factor receptors (FGFR), and insulin-like growth factor type I receptor (IGF-IR).

Endocytosis and endosomal targeting

  1. Top of page
  2. Abstract
  3. Endocytosis and endosomal targeting
  4. RTK signaling: plasma membrane versus endosome
  5. Internalization and retrograde signaling
  6. Degradation versus recycling
  7. Lipid rafts
  8. Conclusions
  9. Acknowledgements
  10. References

Intracellular trafficking of RTKs requires endocytosis and the transit of receptors through endosomal vesicles (Fig. 1). Endosomes represent a variety of intracellular compartments classified by morphology, subcellular localization, pH, and associated proteins (Cavalli et al. 2001; Bishop 2003), such as members of the Rab family of small GTPases, which are involved in the fusion and budding of distinct endosomal vesicles (McLauchlan et al. 1998; Christoforidis et al. 1999). The early endosome is formed from newly internalized membrane vesicles, which shed their clathrin coat and eventually coalesce to form the sorting endosome. It is from the early endosome that receptors are targeted for degradation or recycling.

image

Figure 1.  Schematic of receptor trafficking. See text for description. ee, early endosome; le, late endosome; se, sorting endosome; ly, lysosome; erc, endosomal recycling compartment.

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The degradation pathway leads to the budding of receptor-bound vesicles from the sorting endosome and the subsequent fusion of these membranes with the more acidic late endosome (∼pH 5.0) and a subpopulation of late endosomes, known as multi-vesicular bodies (Mellman et al. 1986; Sorkin and Von Zastrow 2002). Finally, late endosomes fuse with the lysosomal compartment (Tjelle et al. 1998; Hirota et al. 2004), in which cytoplasmic domains of the receptor are no longer accessible to signaling proteins, rendering the receptor signaling incompetent. Moreover, the increasingly acidic lysosomal environment (∼pH 4.0) promotes protein degradation.

The targeting of RTKs to the lysosome is a well-regulated event, as lysosomal degradation is vital for the attenuation of receptor-mediated signaling responses. In fact, deficiencies in the targeting of RTKs to the lysosome result in prolonged signaling and aberrant cell proliferation (Guenou et al. 2006). Lysosomal targeting involves monoubiquitination, a post-translational modification that follows receptor activation at the cell surface. This process involves the addition of a single ubiquitin polypeptide to lysine residues within the receptor cytoplasmic domain via a ubiquitin ligase, and is also known as monoubiquitination (Liu and Altman 1998). On the other hand, polyubiquitination is the addition of ubiquitin polypeptide chains to lysine residues, which targets cytosolic proteins for proteolysis (Fuchs and Neuwirtova 2006). Generally, RTK degradation is regulated through monoubiquitination and targeting to the lysosome, and will be discussed in more detail later in this review.

In contrast to degradation, RTKs can recycle to the plasma membrane. The recycling pathway is divided into: (i) the fast recycling of proteins to the plasma membrane directly from the sorting endosome (Baravalle et al. 2005) and (ii) the slow recycling of proteins to the plasma membrane, which requires transit through the tubular, perinuclear endosomal recycling compartment (Sakai et al. 1998). Trafficking through the endosomal recycling compartment has been extensively described for transferrin and the transferrin receptor (Touret et al. 2003; Bartz et al. 2005), and is also known as the constitutive recycling pathway (Ullrich et al. 1996; Ren et al. 1998).

RTK signaling: plasma membrane versus endosome

  1. Top of page
  2. Abstract
  3. Endocytosis and endosomal targeting
  4. RTK signaling: plasma membrane versus endosome
  5. Internalization and retrograde signaling
  6. Degradation versus recycling
  7. Lipid rafts
  8. Conclusions
  9. Acknowledgements
  10. References

The internalization and trafficking of RTKs after ligand binding originally was hypothesized to desensitize receptors and attenuate signal transduction, as internalized receptors clear ligand from the extracellular milieu and no longer are available for binding. However, evidence that certain RTKs remain bound to ligand within endosomes and that signaling molecules associate with endosomal vesicles lends support to the concept of the ‘signaling endosome’ (Sorkin et al. 1988; Sorkin 2001) in which receptors are catalytically active and are coupled to signal transduction pathways. In fact, distinct signaling pathways can be activated at the plasma membrane versus the endosome. In Chinese hamster ovary cells, blocking internalization of the IGF-IR results in an attenuation of ERK activation, with no affect on the activation of the PI-3K/Akt pathway (Chow et al. 1998). Blocking internalization of the EGFR expressed in HeLa cells similarly decreases ERK activity but also increases protein kinase C (PKC) activity (Vieira et al. 1996). In PC12 cells, nerve growth factor (NGF)-mediated survival is associated with surface localized TrkA via the activation of the PI-3K/Akt pathway, whereas internalized TrkA induces NGF-mediated differentiation via the ERK pathway (Zhang et al. 2000). Together, these studies suggest that activation of specific signal transduction pathways may be spatially segregated such that PI-3K and PKC signaling occur at the cell surface and ERK signaling occurs predominantly in internalized endosomal vesicles. This model is further supported by the observation that the integral membrane phosphatidylinositol bisphosphate, required for the activation of the PI-3K/Akt and PKC signaling pathways, is localized at the plasma membrane (Haugh 2002). In contrast, upstream components of ERK signaling, such as Ras and Shc, are accessible at the plasma membrane and endosomes (Di Guglielmo et al. 1994; Haugh 2002). Although the ERK pathway may be activated globally, evidence suggests that the most potent activation of ERK occurs subsequent to internalization (Kay et al. 1986; Lai et al. 1989; Di Guglielmo et al. 1994).

Although the above studies support the idea that PI-3K/Akt activation occurs at the cell surface, several other lines of evidence contradict the notion that PI-3K/Akt signaling is restricted to the plasma membrane. For example, the inhibition of TrkA internalization in sympathetic neurons leads to a decrease in PI-3K/Akt signaling and cell death (Zhang et al. 2000; Ye et al. 2003). Wang et al. (2004) demonstrated recently that the PDGFR-β activates various signaling pathways within endosomes including PI-3K/Akt in a human hepatocellular carcinoma cell line. This is further supported by evidence that the regulatory subunit of PI-3K, p85, is associated with early endosomes in sensory neurons (Delcroix et al. 2003). Moreover, Akt co-localizes with Trk within intracellular membrane fractions in a brain-derived neurotrophic factor (BDNF)-dependent manner in primary neurons (Yano and Chao 2005). Recently, we also demonstrated that IGF-I stimulated Akt phosphorylation requires IGF-IR internalization in glial progenitors (Romanelli et al. 2007). These data strongly suggest that endosome-bound receptors are competent for signaling in various cell types and that internalization, in some cases, is required for activated receptors to interact with the appropriate signaling complexes. A further example of this process in the nervous system is retrograde signaling.

Internalization and retrograde signaling

  1. Top of page
  2. Abstract
  3. Endocytosis and endosomal targeting
  4. RTK signaling: plasma membrane versus endosome
  5. Internalization and retrograde signaling
  6. Degradation versus recycling
  7. Lipid rafts
  8. Conclusions
  9. Acknowledgements
  10. References

In neurons, the microtubule-dependent transport of Trk from distal axons to cell bodies is necessary to relay signals to the cell body and nucleus, a process termed retrograde signaling (Hendry et al. 1974; Ehlers et al. 1995). Various reports have demonstrated that retrograde signaling of Trk is required for survival of peripheral and central neurons in culture through the activation of ERK5, phosphorylation of the cAMP response element-binding protein, and the consequent initiation of gene transcription (Ye et al. 2003; Heerssen et al. 2004; Valdez et al. 2005). Furthermore, retrograde signaling from dendrites of hippocampal neurons has been linked to long-term potentiation (Patterson et al. 2001). The mechanisms that regulate Trk retrograde signaling are still elusive; however, they are likely highly regulated, as this process must engage microtubule proteins, block the degradation or recycling of internalized receptors, and recruit the appropriate signaling complexes for neuronal survival (Valdez et al. 2005). Recently, a unique mechanism for retrograde transport and signaling has been defined for TrkA in PC12 cells and primary hippocampal neurons, in which receptors are internalized within membrane ruffles independent of clathrin, a process termed macroendocytosis (Valdez et al. 2007). In this study, internalized Trk-endosomes retain association with rab5, a small GTPase involved in the formation of the early endosome (Bucci et al. 1992), which prevents maturation to rab7-positive late endosomes and degradation through the lysosomal pathway. Furthermore, the retention of rab5-positive endosomes promotes sustained NGF-stimulated signaling (Valdez et al. 2005, 2007). These data are consistent with another study performed on peripheral sensory neurons in which retrograde signaling of TrkA occurred in early endosomes (Delcroix et al. 2003). However, data from other studies demonstrate that late endosomes and multivesicular bodies predominantly mediate NGF-retrograde signaling (Saxena et al. 2005a,b). While there are discrepancies in the exact location of TrkA retrograde signaling, the authors of these studies agree that internalization and retrograde trafficking of TrkA is required for neuronal survival.

Interestingly, Valdez et al. (2007) showed that in contrast to Trk, EGFR internalization occurs by a clathrin-dependent mechanism, resulting in transient signaling and subsequent lysosomal degradation. The differences between EGFR and Trk internalization suggest that trafficking through clathrin-dependent or -independent mechanisms may be involved in the differential subcellular targeting of receptors and the spatiotemporal regulation of signal transduction.

Degradation versus recycling

  1. Top of page
  2. Abstract
  3. Endocytosis and endosomal targeting
  4. RTK signaling: plasma membrane versus endosome
  5. Internalization and retrograde signaling
  6. Degradation versus recycling
  7. Lipid rafts
  8. Conclusions
  9. Acknowledgements
  10. References

The decision of whether a receptor is degraded or recycled to the plasma membrane is critical for regulation of signal transduction, as degradation or recycling prevents or promotes receptor availability, respectively. Our previous studies showed that IGF-I stimulates oligodendrocyte (OL) progenitor cell survival through the sustained phosphorylation of the IGF-IR and Akt (Ness and Wood 2002) (Fig. 2a). In contrast, neurotrophin-3 stimulates only a transient phosphorylation of Akt and degradation of its cognate receptor TrkC, with no significant contribution to the long-term survival of OL progenitors (Ness and Wood 2002; Ness et al. 2002) (Fig. 2b). Interestingly, the ability of IGF-I to promote sustained Akt phosphorylation in these cells requires the internalization and recycling of the IGF-IR (Romanelli et al. 2007) (Fig. 3). The mechanisms that target IGF-IR and TrkC for recycling or degradation remain undefined. In this section, we review experimental evidence for sorting signals that determine the subcellular trafficking of various RTKs. These signals include unique amino acids within the receptor sequence, the modification of lysine residues in ubiquitination, and receptor interacting proteins. Additionally, we discuss evidence for ligand-specificity in RTK targeting.

image

Figure 2.  TrkC but not the IGF-IR is down-regulated following ligand stimulation. (a) TrkC phosphorylation and protein levels are down-regulated in response to continuous exposure to NT-3 in oligodendrocyte progenitor cells (OPCs). Late OPCs were treated with or without NT-3 and isolated protein was analyzed for phospho-Trk and total Trk C receptor. NT-3 was replaced in the media 15 min prior to protein isolation at 10 h. Blots of phosphorylated-Trk and total Trk C receptor are shown after 15 min, 2 h, and 10 h treatments (top panel). Left graph shows quantitation of band density expressed as the percentage of Trk phosphorylation. Quantitation of total Trk C (right graph) is expressed as percentage of the 15 min control levels. *< 0.03 versus 10 h CTRL and **< 0.002 versus CTRL. (b) IGF-IRβ phosphorylation and protein levels are maintained during continuous exposure to IGF-I through 48 h. Late OPCs were treated with or without IGF-I and isolated protein was analyzed for IGF-IRβ expression. Blots were stripped and used for analysis of β-actin as a control for equal protein loading. Top panel shows a representative blot of total IGF-IRβ after 22 or 48 h treatment. Left graph shows quantitation of band density expressed as the fold increase in IGF-IR phosphorylation compared with 22 h control. Quantification of total IGF-IR (right graph) is expressed as percentage of 22 h control levels. *< 0.001 versus CTRL and **< 0.05 versus 48 h IGF-I1. [1Reprinted from Mol. Cellular Neurosci. 20, J. K. Ness and T. L. Wood, Insulin-like growth factor I, but not neurotrophin-3, sustains Akt activation and provides long-term protection of immature oligodendrocytes from glutamate-mediated apoptosis, 476–488, 2002, with permission from Elsevier.]

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image

Figure 3.  IGF-IR trafficking in oligodendrocyte progenitors. (a) IGF-I alters IGF-IR surface availability. Cells were serum starved and treated with 1 nM IGF-I or basal media for indicated times. Cells were labeled with 0.3 mg/mL sulfo-NHS-biotin. Total and surface precipitated lysates were processed for sodium dodecyl sulfate–polyacrylamide gel electrophoresis and western blot analysis for IGF-IRβ subunit immunoreactivity. Top panel shows representative western blot. Surface availability of IGF-IRβ is represented as a ratio of surface to total IGF-IRβ and as a percentage of t0 (bottom panel). *< 0.05 versus t0 and **< 0.004 versus t0. Data shown represent the mean ± SEM (= 3).2 (b) Model for IGF-IR trafficking in OPCs based on empirical data and mathematical modeling. IGF-I ligand binding results in phosphorylation and internalization of the IGF-IR. IGF-IR internalization is required for phosphorylation of Akt. The IGF-IR is targeted through Rab11-positive recycling endosomes to the cell surface. The model includes a surface state of the IGF-IR that is unavailable for ligand binding following receptor recycling. For details, see Romanelli et al. (2007). [2Reprinted from J. Biol. Chem. 282, R. J. Romanelli, A. P. Lebeau, C. G. Fulmer, D. A. Lazzaarino, A. Hochberg, T. L. Wood, Insulin-like growth factor type I receptor internalization and recycling mediate the sustained phosphorylation of Akt, 22513–22524, 2007.]

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Receptor sequences for subcellular trafficking

In primary sympathetic neurons, BDNF-stimulated TrkB is targeted for degradation, whereas NGF-stimulated TrkA is targeted for recycling to the plasma membrane, leading to prolonged PI-3K/Akt pathway activation and cell survival (Chen et al. 2005). The authors of this study determined that a juxtamembrane region (amino acids 473–493) of the TrkA, not present in the corresponding TrkB sequence, is necessary and sufficient for receptor recycling. Furthermore, the introduction of this sequence into TrkB leads to receptor recycling and an increase in neuronal survival (Chen et al. 2005).

Interestingly, the recycling domain of TrkA also is absent in the corresponding sequence of TrkC (Fig. 4), which potentially explains the preferential targeting of this receptor for degradation in OL progenitor cells (Ness and Wood 2002). It should also be noted, however, that a homologous recycling domain is absent from the IGF-IR sequence (Romanelli and Wood, unpublished observation). Others also have shown that this domain is absent from the sequence of G protein-coupled receptors that undergo recycling (Cao et al. 1999). Therefore, unique recycling mechanisms exist for various receptor types.

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Figure 4.  Comparison of Trk juxtamembrane recycling domain. Sequence alignment of the juxtamebrane regions of the human TrkA, TrkB, and TrkC (highlighted). TrkA recycling domain is not present in the homologous sequence of TrkB or TrkC.

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Recently, Sorensen et al. (2006) demonstrated that a 50 amino acid sequence downstream of the tyrosine kinase domain in FGFR1 and 4 is required for the transport of fibroblast growth factor (FGF-1) from the plasma membrane to the cytosol and nucleus. Unlike FGFR1 and 4, FGFR2 lacks this sequence and consequently does not transport FGF-1 to the cytosol and nucleus (Sorensen et al. 2006). Interestingly, mutation of two amino acids within FGFR2 (Q774M, P800H) is sufficient to allow FGFR2 to similarly transport FGF-1 (Sorensen et al. 2006).

Taken together, evidence from the Trks and FGFRs suggest that specific sequences are required to target receptors to their appropriate subcellular locations. Further investigation is needed, however, to characterize these receptor sequences and to determine their direct role in receptor trafficking. It is tempting to speculate that these sequences confer interactions with known or yet unidentified trafficking proteins.

Receptor interacting proteins

There is a rapidly expanding list of receptor interacting proteins, known to regulate receptor-stimulated signal transduction. In this section, we review recently identified proteins that associate with RTKs and influence signal transduction through modulation of receptor trafficking.

GAIP-interacting protein, C-terminus (GIPC) is a PDZ-domain containing protein that binds to G alpha interacting protein (GAP or GTPase-activating protein for heterotrimeric G proteins) (De Vries et al. 1998). GIPC interacts with the juxtamembrane region of TrkA (Liu et al. 2001). Characterization of this interaction demonstrated that knock-down of GIPC results in the slowed internalization and retrograde trafficking of TrkA, as well as in the inhibition of NGF-mediated Akt and ERK phosphorylation (Varsano et al. 2006). The Xenopus homolog of mammalian GIPC, xGIPC, or Kermit 2, also has been implicated in IGF-IR signaling by directly interacting with the IGF-IR and promoting IGF-I stimulated MAPK signaling and Xenopus oocyte maturation (Booth et al. 2002). More recently, Wu et al. (2006) demonstrated that xGIPC is required for sustained, but not short-term, activation of the PI-3K/Akt signaling pathway in the Xenopus embryo. Furthermore, dominant-negative IGF-IR or depletion of xGIPC inhibits Xenopus eye development (Wu et al. 2006). This recent study exemplifies that short- and long-term signal transduction is distinctly regulated and results in different biological outcomes. Based on evidence for the involvement of GIPC in endocytic trafficking, Wu et al. (2006) hypothesized that xGIPC promotes IGF-IR recycling and, consequently, is required for sustained signal transduction and Xenopus eye development. This hypothesis is consistent with our demonstration of sustained PI3-K/Akt signaling in glial progenitors through IGF-IR recycling (Romanelli et al. 2007). Although gaps remain in understanding precisely how GIPC regulates RTKs, this receptor-interacting protein has emerged as an interesting target for investigation of RTK trafficking, the regulation of signal transduction and resultant cellular responses.

Shao et al. (2002) identified pincher (pinocytic chaperone) as a mediator of endocytosis and trafficking of NGF and its receptor TrkA. Over-expression of pincher in PC12 cells stimulates NGF-mediated TrkA endocytosis, whereas expression of a dominant-negative pincher inhibits TrkA internalization (Shao et al. 2002). Furthermore, this mutant selectively inhibits ERK5 but not ERK1/2 phosphorylation (Shao et al. 2002). The results of this study suggest that pincher-mediated trafficking regulates the selective activation of ERK pathways through TrkA. More recently, Valdez et al. (2007) demonstrated that pincher-mediated trafficking of TrkA is required for retrograde trafficking and neuronal survival.

Ubiquitination: a sorting signal for degradation

As previously mentioned, monoubiquitination is a post-translational modification that targets transmembrane receptors for lysosomal degradation, whereas polyubiquitination targets cytosolic proteins for proteolysis (Fuchs and Neuwirtova 2006). Cbl is the major ubiquitin ligase for the monoubiquitination of RTKs and is an important modulator for RTK signaling and anti-oncogenesis, as the down-regulation of cbl can lead to the dysregulation of signal transduction and aberrant cell proliferation (Guenou et al. 2006). Cbl-induced ubiquitination is required for the exit of the EGFR from the early endosome and for fusion of these vesicles with the late endosome (Ravid et al. 2004). In Chinese hamster ovary cells, the targeting of the homologous FGFR subtypes FGFR1 and 4 to lysosomal or recycling vesicles, respectively, has been attributed to several conserved lysine residues within the sequence of FGFR1 (Haugsten et al. 2005).

Ubiquitination of transmembrane receptors also is associated with the recruitment of proteins that carry ‘ubiquitin interacting motifs,’ including hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) (Komada and Kitamura 1995; Raiborg et al. 2002). Hrs associates with EGFR-bound early endosomes and regulates EGFR delivery to late endosomes (Kim et al. 2007). Moreover, Sprouty, a negative regulatory of RTK signaling and a tumor suppressor (Kim and Bar-Sagi 2004; Mason et al. 2006), interacts with the EGFR-Hrs-endosomal complex preventing the delivery of the EGFR to the late endosome and impairing EGFR-induced ERK activation (Chin et al. 2001; Kim et al. 2007). The authors of this study reasoned that trafficking of the EGFR through the early and late endosome is required for appropriate signaling responses. Thus, cbl-mediated ubiquitination and the consequent recruitment of ubiquitin-interacting protein complexes is required for the fidelity of EGFR signaling and the ultimate degradation of this receptor.

Ligand-dependent RTK trafficking

The above evidence suggests that the determination of whether a RTK is recycled or degraded is dependent upon amino acid sequences within the receptor and/or proteins that may interact with or modify specific amino acid residues. Multiple lines of evidence, however, demonstrate that the subcellular targeting of RTKs also can be dependent on ligand specificity. For example, whereas transforming growth factor α (TGFα) and epidermal growth factor (EGF) bind to the EGFR with similar affinities (Massague 1983; Lax et al. 1988), TGFα binding induces receptor recycling and EGF binding induces receptor degradation (Ebner and Derynck 1991; French et al. 1995). Ebner and Derynck (1991) determined that the ligand-specific differences in EGFR trafficking are due to the sensitivity of individual ligands to pH. In this study, the authors showed that TGFα/EGFR interactions are sensitive to low pH, resulting in dissociation of ligand–receptor complexes during transit through increasingly acidic endosomal vesicles. In contrast, EGF is less sensitive to pH and therefore, this ligand remains bound to the receptor after internalization (Ebner and Derynck 1991). Interestingly, the signaling properties of TGFα are more potent than EGF (Myrdal et al. 1986), as both ligands stimulate mitogenesis, but TGFα signaling is more likely to lead to cellular transformation and tumorigenisis (Salomon et al. 1990). This difference in potency is likely because of TGFα-mediated recycling of the EGFR and sustained signal transduction. Consistent with this idea, a mutant insulin receptor (IR) that has increased binding to insulin in an acidic endosomal environment was identified in a patient with severe insulin resistant diabetes (Taylor et al. 1990). Consequently, the receptor mutant is degraded rather than recycled to the plasma membrane (Taylor et al. 1990). Based on these experimental and clinical data, it is postulated that ligands may be modified to achieve desired changes in intracellular trafficking and thereby preferentially modify biological responses (French et al. 1995).

Nerve growth factor signaling provides another example of the role of specific ligand-receptor interactions in the regulation of receptor targeting. NGF binds to both TrkA and the p75NTR. These receptors are internalized in response to NGF stimulation; however, the p75NTR recycles to the plasma membrane whereas TrkA is degraded (Saxena et al. 2005b). Interestingly, NGF–TrkA interactions are resistant to endosomal acidification (Zapf-Colby and Olefsky 1998), which likely is responsible for the targeting of TrkA for degradation. Together these data support the idea that strong ligand–receptor interactions target receptors for degradation, attenuating the signaling response, whereas weaker ligand–receptor interactions target a receptor for recycling, augmenting the signaling response. Therefore, ligand specificity plays a vital role in the regulation of receptor trafficking and signal responses.

Lipid rafts

  1. Top of page
  2. Abstract
  3. Endocytosis and endosomal targeting
  4. RTK signaling: plasma membrane versus endosome
  5. Internalization and retrograde signaling
  6. Degradation versus recycling
  7. Lipid rafts
  8. Conclusions
  9. Acknowledgements
  10. References

We have focused thus far on the mechanisms that regulate the trafficking of RTKs from the plasma membrane to intracellular subcellular compartments, and how trafficking plays a central role in the activation of specific signal transduction pathways and cellular responses. In this section, we discuss lateral trafficking of RTKs to plasma membrane microdomains known as lipid rafts, and the role of lipid rafts in RTK-stimulated signal transduction and subcellular trafficking,

Lipid raft structure and function

The traditional view of the plasma membrane as a random assortment of proteins and lipids has been challenged by the discovery of structured microdomains, termed lipid rafts. Lipid rafts are relatively small regions of the plasma membrane (∼25–50 nm in diameter) enriched in saturated phospholipids, glycosphingolipids, and cholesterol, which promote a liquid order that is less fluid than the surrounding plasma membrane (Pralle et al. 2000; Pike 2005). Taking advantage of the lipophilic properties of such microdomains, lipid rafts can be isolated based on their insolubility in mild non-ionic detergents (e.g. Triton X-100) at 4°C. Subsequently, insoluble membranes can be purified by sucrose density centrifugation, as lipid rafts are buoyant at low sucrose densities (London and Brown 2000). Lipid rafts have been implicated in a variety of processes, including the regulation of protein and lipid trafficking, cellular polarity, endocytosis, and signal transduction (Sprong et al. 2001; Manes et al. 2003; Nabi and Le 2003). Proteomic analysis of lipid raft microdomains from PC12 cells demonstrates that protein kinases/phosphatases and heterotrimeric G proteins are concentrated in these membranes (Foster et al. 2003). Various reports have shown also that RTKs and glycophosphatidylinositol-anchored proteins localize within lipid rafts. The cholesterol-depleting agent methyl-β-cyclodextrin (MβCD) and various cholesterol biosynthesis inhibitors disrupt lipid raft structure and the association of raft proteins, altering signal transduction pathways in many cell types (Holleran et al. 2003; Buk et al. 2004). Based on these studies, it is hypothesized that membrane cholesterol is required for lipid raft structure and that lipid rafts compartmentalize receptors and second messengers for the spatiotemporal regulation of signal transduction. In fact, it is postulated that lipid rafts provide a putative platform for the formation of receptor-signaling complexes (Fig. 5).

image

Figure 5.  Lipid rafts promote the formation of receptor-signaling complexes. Saturated phospholipids preferentially interact with cholesterol and modified hydrophobic proteins (including acylated and glycophosphatidylinositol-anchored proteins), as well as various kinases and phosphatases in microdomains termed lipid rafts. Upon activation, RTKs can translocate into lipid rafts, promoting the activation of various signal transduction pathways through the formation of receptor-signaling complexes.

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A subset of lipid rafts, termed caveolae, is characterized by the presence of the integral membrane protein caveolin (Rothberg et al. 1992). The association of caveolin with lipid rafts induces the formation of flask-like invaginations of the plasma membrane, first identified by electron microscopy (Palade 1953; Yamada 1955). In contrast to caveolae, non-caveolae ‘flat’ rafts are morphologically featureless.

Function of lipid rafts in neural cells

In the brain, lipid rafts concentrate and organize cell adhesion molecules and cytoskeletal machinery for axonal growth and guidance (Guirland et al. 2004; Kamiguchi 2006). The localization of the calcium/calmodulin-dependent protein kinase (CaMK)-like CREB kinase III (CLICK-III) in lipid rafts promotes dendritogenesis of cortical neurons in vitro (Takemoto-Kimura et al. 2007). Furthermore, calcium channel localization within lipid rafts in neurons from the cerebellum regulates channel conductance (Taverna et al. 2004; Davies et al. 2006). Recently, the NMDA receptor was found increasingly associated with lipid rafts in the rat brain during development (Besshoh et al. 2007). There is also evidence that pre-synaptic superfamily of N-ethylmaleimide-sensitive factor adaptor protein receptor (SNARE) proteins, which regulate exocytosis, are localized to lipid rafts in PC12 cells (Chamberlain et al. 2001). Caveolae mediate cell shape in OLs through interactions with actin-binding proteins at the onset of myelination (Taguchi et al. 2005). Moreover, lipid rafts are concentrated within myelin, which is unsurprising as myelin is enriched with glycosphingolipids, sulfatides, and cholesterol (Dietschy and Turley 2001; Marcus and Popko 2002). Taken together, these studies demonstrate potentially important and unique roles for lipid raft microdomains in neurons and glia.

Lipid rafts and RTK signaling and trafficking

Receptor tyrosine kinases localize within caveolae by direct interaction with caveolin through a putative caveolin-binding motif within their tyrosine kinase domain (Couet et al. 1997b; Nystrom et al. 1999). RTKs including the EGFR, PDGFR, ErbB, IR, and IGF-IR localize within caveolae in various cell types (Biedi et al. 2003; Matthews et al. 2005). Whereas most RTKs translocate into caveolae upon agonist stimulation, the EGFR moves out of caveolae in the presence of ligand (Mineo et al. 1999). Furthermore, disruption of caveolae structure via MβCD augments, rather than attenuates, EGFR signaling (Couet et al. 1997a; Engelman et al. 1998). Interestingly, caveolae negatively regulate IR signaling in undifferentiated pre-adipocytes but positively regulate IR signaling in mature adipocytes (Nystrom et al. 1999). Therefore, the role of caveolae in the regulation of RTK mediated signaling is dependent upon the specific RTK, as well as the state of cellular differentiation.

The glial cell line-derived neurotrophic factor receptor Ret, a member of the RTK family, translocates into lipid rafts upon ligand stimulation. Interestingly, translocation into lipid rafts protects Ret from ubiquitination and consequential targeting for degradation (Pierchala et al. 2006). These data suggest that lipid rafts promote receptor longevity, such that ubiquitin ligases and the cellular machinery that regulate ubiquitination may have restricted access to lipid rafts. It remains to be determined, however, if this is a common mechanism by which RTKs avoid degradation.

Decker and ffrench-Constant (2004) showed that PDGF-stimulated PI-3K/Akt pathway activation occurs within lipid rafts of newly differentiated OLs and that co-localization of PDGFR-α and α6β1 integrins within lipid rafts amplifies the activity of this survival pathway. The conclusion from this study is that the disruption of lipid rafts blocks PDGFR-α and integrin co-localization and results in decreased PDGF-mediated cell survival. Similarly, disruption of lipid rafts in a fibroblast cell line results in the displacement of the IGF-IR and a decrease in IGF-I mediated protection from apoptosis with no effect on IGF-I stimulated proliferation (Matthews et al. 2005). These biological outcomes are correlated with increased ERK phosphorylation and decreased Akt phosphorylation (Matthews et al. 2005).

ErbB4, a member of the RTK family that binds neuregulin (NRG), also localizes to lipid rafts in a ligand-dependent manner in primary cortical neuronal cultures and human embryonic kidney (HEK293) cells (Ma et al. 2003). Moreover, disruption of lipid rafts inhibits NRG-induced activation of ERK and prevents NRG-induced blockade of long-term potentiation at synapses in hippocampal slices (Ma et al. 2003).

Together, these findings support the hypothesis that compartmentalization of RTKs within lipid rafts regulates the spatiotemporal activation of signal transduction and resultant biological outcomes.

Caveolae and internalization

As previously mentioned, clathrin-independent mechanisms of receptor internalization have been described, including macropinocytosis and caveolae-dependent internalization (Hibbert et al. 2006; Echarri et al. 2007; Valdez et al. 2007). The latter involves protein sequestration into internalized caveosomes in a dynamin-dependent manner (Lajoie and Nabi 2007). Recent studies suggest that the mechanism of internalization is important for regulating specific cellular responses. Hibbert et al. (2006) showed that BDNF-p75NTR complexes internalize through either clathrin or caveolar-dependent mechanisms, resulting in degradation of p75NTR and apoptosis of sympathetic neurons. In contrast, NGF-TrkA complexes internalize exclusively through a clathrin-dependent mechanism, resulting in survival and axonal growth of sympathetic neurons (Hibbert et al. 2006). Similarly, Di Guglielmo et al. (2003) demonstrated that internalization of the TGFβ receptor through clathrin-dependent trafficking is associated with early endosome signaling, whereas caveolae-dependent trafficking of this receptor is associated with degradation (Di Guglielmo et al. 2003). Whereas the EGFR is internalized classically through clathrin-dependent endocytosis, high-doses of EGF stimulate ubiquitination and the endocytosis of the EGFR through caveolae in HeLa cells (Sigismund et al. 2005). It is likely that internalization through caveolae rather than clathrin, in the presence of high-doses of ligand, serves as a mechanism to attenuate EGFR signaling responses from the endosome. Together, these data suggest that endocytosis of RTKs through different internalization pathways confer differences in resultant receptor targeting and cellular responses.

Conclusions

  1. Top of page
  2. Abstract
  3. Endocytosis and endosomal targeting
  4. RTK signaling: plasma membrane versus endosome
  5. Internalization and retrograde signaling
  6. Degradation versus recycling
  7. Lipid rafts
  8. Conclusions
  9. Acknowledgements
  10. References

Receptor tyrosine kinases mediate diverse processes within the developing and adult brain. In this review, we provide various lines of evidence to suggest that trafficking of RTKs is required for the specificity and fidelity of signal transduction and consequent biological responses within neural cells. It is clear from these studies that the segregation of signaling complexes and the appropriate delivery of RTKs to these complexes is highly regulated through mechanisms including receptor-sorting sequences, adaptor proteins, specific ligand–receptor interactions, and lipid raft microdomains. These mechanisms also modulate RTK activity and longevity by determining whether a receptor is recycled, degraded, or retrogradely transported. Importantly, a better understand of the mechanisms that control RTK trafficking may contribute to the design of novel therapeutics to modulate signaling pathways in disease-states in the brain.

Most notably, RTKs have been the target of therapeutics used to treat tumors from various cellular origins (Kim et al. 2004; Reinmuth et al. 2006; Wang et al. 2006). The strategy to date has been to initiate or block signaling with molecules that act as receptor agonists or antagonists or that directly targets the signaling pathways of interest. A more sophisticated approach, which is highlighted in this review, points to the notion of designer molecules that act at specific amino acid residues of a receptor or on receptor-associated proteins to alter the subcellular targeting of RTKs, and consequently fine-tune signaling responses. Alternatively, and as described earlier, modified ligands may be designed to alter their affinity to RTKs, thus changing their subcellular targeting and the consequent strength and duration of signal transduction. One example of this is the discovery that monoclonal antibodies designed to inhibit the IGF-IR alter receptor trafficking by high affinity binding, promoting receptor degradation, and consequently preventing human tumor growth in vivo (Burtrum et al. 2003).

The use of such designer molecules can be applied not only to treating brain tumors but to other neurological disorders, such as psychiatric and neurodegenerative diseases that are associated with impaired synaptic function or neuronal survival. Future therapies might modulate these processes through RTK trafficking and signaling responses.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Endocytosis and endosomal targeting
  4. RTK signaling: plasma membrane versus endosome
  5. Internalization and retrograde signaling
  6. Degradation versus recycling
  7. Lipid rafts
  8. Conclusions
  9. Acknowledgements
  10. References

This work was supported by National Institute of Neurological Disorders and Stroke, National Institutes of Health Grants NS37560 and NS050742 to TLW.

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  4. RTK signaling: plasma membrane versus endosome
  5. Internalization and retrograde signaling
  6. Degradation versus recycling
  7. Lipid rafts
  8. Conclusions
  9. Acknowledgements
  10. References
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