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New Perspectives in Shh Signalling?

*.

* Corresponding Author: Immunobiology Group, Centre for Inflammation Research, University of Edinburgh, Teviot Place, EH8 9AG, Scotland, U.K. Email: carolyn.fisher@ed.ac.uk

The Shh-Ptc signalling pathway and its components have been the subject of much research. Previous chapters of this book have illustrated the importance of this pathway and its activation in many aspects of development, regeneration of adult organs, and pathology. The role of Ptc as the primary receptor for Shh and its analogues has been emphasised in these chapters. However, there is mounting evidence that megalin [also known as glycoprotein 330 (gp330) or low-density lipoprotein receptor-related protein 2 (LPR2)], a 600kDa transmembrane glycoprotein belonging to the low density lipoprotein (LDL) receptor family, may be a second receptor for Shh. In this chapter I shall review this evidence; but I shall preface this discussion with an outline of the known properties and biological functions of megalin.

Megalin

Megalin (gp330) was first discovered in 1982 as the pathogenic antigen of Heymann nephritis.1 The megalin gene has been sequenced in rat and human2,3and mapped to chromosome 2.4 The protein contains a single transmembrane domain,4 is known to act as an endocytic receptor and is expressed primarily in polarised epithelial cells, and strictly on the apical surfaces of such cells.5Both the protein and its mRNA have been identified in human parathyroid cells, placental cytotrophoblasts and epididymal epithelial cells. The protein is also expressed in mammary epithelia, thyroid follicular cells, yolk sacs, the ciliary body of the eye,6the intestinal brush border,7the male reproductive tract,8uterus and oviduct,9and gallbladder epithelium.10 In addition, immortalised foetal rat alveolar pretype II cells,11adult rat type II pneumocytes12,13 and human type II cells14have all been reported to express megalin. It has been proposed that in adult lung megalin may be important in supplying vitamin E to type II pneumocytes.15

The functions of megalin have been studied in greatest detail in the renal proximal tubule, where it is expressed in the luminal aspects of epithelial cells, and is associated with the sodium-potassium exchanger.16It is also involved in renal uptake of angiotensin17 and the reabsorption of various molecules including calcium18and vitamin D.19

Cubilin

Interactions between megalin and scaffold proteins, usually mediated through cytosolic adaptors, imply a diversity of functions in cellular communication and signal transduction as well as endocytosis.20The 460 kDa receptor protein cubilin (gp 280), which has been sequenced in human21and other species, is required for megalin-dependent endocytosis of many ligands in kidney tubules and other epithelial types.22-27Cubilin is a peripheral protein, attached to the extracellular face of the epithelial cell membrane by its 110-residue N-terminal sequence,28which contains numerous EGF-like, complement (C1r/C1s)-like and bone morphogenic protein-like repeats.29In neonate and adult mice, there is significant overlap between expression of the cubilin and megalin transcripts.23However, cubilin is more restricted in distribution than megalin.30

Endocytosis: RAP and Other Adaptor Molecules

The polarised distribution of megalin in epithelial cells results from interactions involving its cytoplasmic (C-terminal) moiety.31Several adaptor molecules that bind the cytoplasmic tail of megalin to intracellular proteins have been identified including autosomal recessive hypercholesterolemia (ARH), which facilitates megalin-related endocytosis and might serve as a chaperone during internalization.32ARH colocalizes with megalin in clathrin coated pits and in recycling endosomes in the Golgi. Internalised megalin is first seen together with ARH in clathrin coated pits. Then, in sequence, it is seen in early endosomes, pericentriolar tubular recycling endosomes, and finally the cell surface again.

Trafficking through early endosomes might be characteristic of ligand-bound megalin, but in the absence of ligands this process involves the receptor-associated protein, RAP, in humans and rats;33,34the mouse homologue is heparin binding protein-44.35 Megalin-RAP complexes appear to cycle through the late endosomes. From these, megalin is returned to the cell surface while RAP is degraded in the lysosomes.36 RAP has a chaperone-like function necessary for normal processing and subcellular distribution of megalin. Without RAP, megalin levels in the cell fall significantly; in kidney proximal tubule cells, less is detected on the brush-border membrane and relatively more on the rough endoplasmic reticulum.37

Megalin-RAP Binding

In humans, RAP is a 39 kDa protein that copurifies with megalin,38,39binds to it with high affinity (Kd = 8nM), and colocalises with it on the apical surfaces of renal tubular epithelial cells.38 In rats, RAP is a 44 kDa molecule.39 Binding of RAP to megalin is calcium-dependant.40,41Direct binding studies show that there are two primary megalin binding sites within RAP; one between amino acids 85 and 148, and the other between amino acids 178 and 248.42

Orlando et al43demonstrated that amino acids 1111-1210 represent a binding site on megalin for various ligands including RAP and concluded that there was one common binding site for several ligands. A specific anti-megalin Ab causes only partial inhibition of RAP-binding to megalin43and a more recent study suggests that megalin has more than one binding site for RAP;44however, the stoichiometry is unknown.38Multiple RAP-binding sites on megalin would be consistent with the fact that the most closely-related member of the LDLR family, LDL receptor-related protein (LRP), which is very similar to megalin in overall structural organisation, function and size,5,45has multiple RAP-binding sites.46

Megalin-Shh-RAP Interactions

Megalin is known to interact with a multitude of molecules, most notably cubilin. However, there is now in vitro evidence that Shh and megalin interact. A radiolabelled ligand binding assay and ELISA showed that N-Shh binds megalin with high affinity. In addition, surface plasmon resonance (SPR) measurements showed that a recombinant fusion protein of N-Shh with glutathione-S-transferase (GST-N-Shh) was able to bind megalin with an affinity constant (KD) of 21nM in the presence of calcium; in control experiments recombinant GST did not bind to megalin.44

Possible interactions among RAP, megalin and Shh were investigated in BN (rat yolk sac cell-line) cells, where it was established that megalin was the only RAP-binding member of the LDLR family present.44When these cells were cultured in the presence of GST, intracellular punctate staining consistent with vesicular localisation of GST-N-Shh was evident; addition of RAP, or anti-megalin antibodies, blocked GST-N-Shh uptake. This implies communication among these molecules at some level, and confirms that RAP is a specific inhibitor of megalin in this system. As mentioned earlier, megalin endocytoses its ligands. It has been argued that this leads to lysosomal degradation, evidenced by the presence of TCA-soluble proteolytic fragments of ligands in media after in vitro culture.11In contrast, megalin-N-Shh appears resistant to dissociation at pH 4.5, implying stability in the acidic environment of endosomes; moreover, chloroquine (a lysosomal proteinase inhibitor) does not inhibit32 P-labelled GST-N-Shh degradation in BN cells.44 How some megalin ligands appear to bypass lysosomal degradation is not clear at present.

Megalin in Development: More Links to Shh

Megalin is expressed on the outer cells of the preimplantation mouse embryo during epithelial differentiation, suggesting a role in early embryo development.47Not surprisingly, it participates in the development of the renal proximal tubule,48and it is important in development of the forebrain.49Megalin-cubilin complexes might be important in placental transport, since application of antibodies to pregnant females has teratogenic effects.50However, megalin and cubilin have different expression patterns in the mouse embryo.51

Many developmental abnormalities in mice that lack components of the Shh pathway are strikingly similar to those found in megalin -/- mice, suggesting that megalin is a regulatory component of the Shh signalling pathway.52Shh -/- and smo -/- mice, smo -/- zebrafish embryos, mice lacking dispatched (Disp), which is critical for the secretion/long-range signalling of N-Shh, and partially rescued Ptc -/- embryos, all display neurodevelopmental abnormalities. 53Shh and megalin are coexpressed early in the development of the nervous system, and megalin-containing cells internalise the active fragment N-Shh by a mechanism sensitive to anti-megalin antibodies. N-Shh uptake may also be dependent on heparan-sulphate-containing-proteoglycans.44 McCarthy and Argraves53have proposed possible models for the role of megalin in the neurodevelopmental biology of Shh and retinol. N-Shh might signal directly via megalin; it might be internalised by megalin-dependent endocytosis to regulate its availability to Ptc, or in order to deliver it to vesicular pools of Ptc;54or it might undergo transcytosis while megalin internalises Ptc and smo.

Proteoglycans and Megalin Interactions

Although heparan sulphate proteoglycans (HSPGs) have been implicated in megalin function, 44there is no direct interaction; megalin does not specifically bind heparin.55RAP possesses binding sites for both megalin and heparin; the heparin-binding site on RAP is between amino acids 261 and 323.42The megalin and heparin binding sites within RAP are noncontiguous, consistent with the view that the glycosominoglycan site is physiologically exposed when RAP is bound to megalin.42 Therefore it is conceivable that megalin requires the aid of a ligand, such as cell-surface expressed RAP, in order to interact with HSPGs for signalling purposes; alternatively HSPGs might be required for megalin to bind to certain ligands, as evidenced in the thyroid. The Transcytosis of thyroglobulin (Tg) via megalin within the thyroid gland involves HSPGs, and it has been demonstrated that HSPGs bind to the heparin-binding sequence on Tg (between amino acids 2489 and 2503 in rat), facilitating the binding of this prohormone to megalin, and ultimately its transcytosis.56

Lung Development and the Role of Megalin

Pulmonary development begins in the mouse at embryonic day (E) 9-9.5 as an endodermal budding from the foregut; two endodermal buds (primary buds) give rise to the left and right lobes of the distal lung. Initially the primary bronchial buds divide asymmetrically, growing ventrally and caudally. Not until E10.5 does lateral branching begin, leading to one left and four right secondary bronchi. As morphogenesis continues, dichotomous branching ensues. Four morphological stages of lung morphogenesis in mammals have been described.57,58In mice, the pseudoglandular phase, characterised by dichotomous branching and the establishment of the basic branching pattern of the lungs, begins at E11.5 and ends at approximately E16. The canalicular phase then ensues with centrifugal branching (radially outward from the centre) forming the bronchial airways. E19 signifies the end of the saccular phase, which like the canalicular phase involves centrifugal branching, and results in the formation of distal branches linked to alveolar sacs. The final stage of lung morphogenesis is termed the alveolar phase; mature alveoli are formed by outpouching of alveolar sacs. In mice (and rats) alveolar maturation is an entirely postnatal event.59

Whilst the most noticeable abnormalities in megalin-deficient embryos involve the CNS, Willnow et al49reported developmental abnormalities in both kidney and lung in megalin-deficient mice. Megalin knockout mice die perinatally of respiratory insufficiency and show abnormalities in epithelia that normally express the protein. In particular, immunohistochemical analysis of the lungs reveals emphysematous areas characterised by enlarged alveoli, and atelectic regions defined by collapsed alveoli and thickened alveolar walls.49

Although it has long been known that Shh is expressed in lung during mammalian pulmonary development, the only published evidence that megalin is also expressed during pulmonary development was reported by Kounnas et al5who found megalin in the bronchial epithelia of E12.5 murine lungs. Its possible role in pulmonary development has not been investigated until now. Just as Shh expression becomes restricted as pulmonary development progresses, so does megalin expression. Moreover, not only do the expression patterns of the two molecules appear similar but also megalin and Shh are coexpressed in the same cells during pulmonary development (fig. 1). This probably represents colocalisation, though as yet the evidence is circumstantial.

Figure 1. Coexpression of Shh and Megalin During Murin Pulmonary Development.

Figure 1

Coexpression of Shh and Megalin During Murin Pulmonary Development. The epithelia of embryonic airways express sonic hedgehog protein (A), demonstrated here with chromogenic DAB-based staining; megalin protein is also expressed in some epithelial airway (more...)

Although mRNA transcripts for megalin are found in adult mouse lung, there is no coexpression of cubilin.23Therefore if megalin is involved in the transport/endocytosis of Shh in this organ, it either does this in isolation or an alternative ligand must be involved. One possible candidate is RAP. RAP is most abundant in the lumen of the ER, but immunohistochemistry and cell surface radioiodination have been used to demonstrate its presence on the apical surface of renal proximal tubule cells,60gingival fibroblasts61and two carcinoma cell-lines.55,62Biochemical studies have shown that RAP present on the surface of cells, or exogenous RAP added to culture, is an effective inhibitor of ligand binding to megalin and LRP. HBP-44 mRNA is present during murine pulmonary morphogenesis63 and although a study of the immunolocalisation of megalin and RAP proteins during murine embryogenesis, did not determine whether RAP was present in lung,5there is no evidence to the contrary. Indeed, the greatest problem facing researchers intent on studying RAP protein expression in the mouse is the nonavailability, to date, of any specific antibody (personal communications). However, it is likely that RAP protein (HBP-44) is expressed in murine lung, as evidenced by the presence of mRNA.

All seven types of glycosaminoglycans (GAGs) are found within the lungs of postnatal rats,64 sulphated GAGs are present during chick lung development,65and heparin is thought to modulate the kinetics of heparan sulphate binding ligands that drive lung development.66Coupled with the observations that megalin and Shh are expressed within the same cells during development of the mouse pulmonary system, and that there is a conserved sequence within Shh for binding heparan containing PGs that is distinct from the binding site for Ptc,67this invites conjecture about how all these molecules interact.

At least three models of possible Shh-megalin interactions during neurodevelopment have been proposed by McCarthy and Argraves,53though whether megalin constitutes a component of the Shh pathway is not clear.

  1. N-Shh signals directly via megalin. In the thyroid, HSPGs aid the binding of megalin to its ligands.56 By analogy, it could be argued that in those lung cells that coexpress Shh and megalin, HSPGs are bound by Shh, which then facilitates binding to megalin, allowing signalling to ensue. A similar model for Shh binding to Ptc has been proposed54 on the evidence that HSPGs synthesised by the enzymatic action of tout velu regulate Shh movement.68
  2. The observation that Shh can be internalised by megalin-containing cells during development of the CNS, and the work of44 on BN cells, give credence to the possibility that N-Shh might be internalised by megalin-dependent endocytosis, a process reliant on RAP. Although there is no conclusive evidence that RAP protein is expressed in lung, the presence of HBP-44 mRNA suggests that it is likely.
  3. N-Shh might undergo transcytosis while megalin internalises Ptc and smo. This would imply that megalin is either a component of the Shh pathway or that it interacts with various elements of it.

The Good, the Bad, and the Ugly

As with all relatively new discoveries and models, the interaction(s) between megalin and Shh, the cross-talk between megalin and other components of the Shh signalling network such as Ptc and smo, and the hypothesis that megalin constitutes a regulatory component of the Shh pathway, are by no means fully detailed or articulated.

During mouse embryogenesis, many sites of megalin expression are either identical to those expressing Shh or located in adjacent tissues regulated by Shh signalling,44 suggesting interaction at some level. Most of the work aimed at elucidating interactions between Shh and megalin has concentrated on development of the CNS, where coexpression of the molecules has been demonstrated. Such studies, and the ex-vivo study of44investigating megalin-Shh interactions in BN cells, strengthens the suggestion made by Herz and Bock52that megalin is a component of the Shh signalling pathway. Indeed, when comparisons are made among the abnormalities prevalent in the CNS of Shh -/- mice, megalin KO mice and embryos lacking other components of the Shh signalling cascade, significant crossover is apparent. Since megalin and Shh are also coexpressed during development of the murine pulmonary system, it is tempting to speculate that the interactions demonstrated during neurodevelopment are conserved across different organs, and possibly different species.

However, while there is evidence that Shh and megalin are coexpressed during pulmonary development, just as they are during development of the CNS, the data concerning lung organogenesis from KO studies do not directly implicate megalin in the Shh pathway. Shh -/- mice essentially have no lungs; it is an embryonic lethal phenotype. Megalin -/- mice die perinatally due to respiratory insufficiency, lungs do form but there appear to be problems with differentiation/specialisation. This suggests that even if megalin acts as a second receptor for Shh during early lung development, in conjunction with the primary receptor Ptc, it is neither sufficient nor indispensable for lung branching morphogenesis. In addition, the phenotypic evidence from studies on KO mice clearly indicate that megalin cannot be substituted for Ptc or Shh i.e., this is not an example of redundancy in nature. The most plausible conclusion from this evidence is that the function(s) of megalin during pulmonary morphogenesis is (are) unrelated to the Shh pathway. This of course does not preclude interactions between these molecules, or the possibility that Shh is a ligand for megalin, but it challenges the view that megalin is a component of the Shh pathway.

There are data suggesting that Shh and megalin directly interact, and phenotypic data strongly indicating that megalin constitutes a member of the Shh signalling pathway (the ‘good’). But there are also data inconsistent with this conclusion (the ‘bad’), leaving us with conflicting information and a need for clarification (the ‘ugly’). Such confusion is inevitable at this stage; the Shh pathway/network has not been fully elucidated. It will not be an easy task to integrate our understanding of this pathway with megalin, a very versatile protein that interacts with a vast number of ligands and serves many different functions that remain incompletely understood. It is clear that the importance of Shh-megalin interactions varies among different organs, as does the relative importance of the individual proteins at different stages of development. Further research will be required to elucidate these interactions.

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