The Rate of Internalization of the Mannose 6-Phosphate/Insulin-like Growth Factor II Receptor Is Enhanced by Multivalent Ligand Binding

York, Sally J.; Arneson, Lynne S.; Gregory, Walter; Dahms, Nancy M.; Kornfeld, Stuart

doi:10.1074/jbc.274.2.1164

Cited by 105 publications

(123 citation statements)

References 47 publications

Supporting

Mentioning

117

Contrasting

Unclassified

Order By: Relevance

“…Considering that the high affinity of this compound did not arise from a bivalent M6P-based binding mechanism, it is not surprising that York et al found that the compound failed to stabilize the receptor's dimeric structure or to stimulate its rapid internalization. 5 In summary, there is currently no evidence in the literature of a small synthetic compound capable of bivalent binding to the M6P/IGF2R by a M6P-based mechanism.…”

mentioning

confidence: 97%

“…3 Binding of high-affinity, M6P-based ligands and rapid internalization of extracellular ligands, such as IGF-II, are aided by the M6P/IGF2R's ability to dimerize. 4,5 York et al demonstrated that β-glucuronidase (hGUS), a homotetrameric lysosomal enzyme bearing multiple M6P moieties, stabilized the receptor's dimeric structure by cross-bridging the M6P binding sites on two adjacent subunits. 5 These data support a dimeric model for binding of bivalent M6P-based ligands by the M6P/IGF2R (Figure 1).…”

mentioning

confidence: 99%

“…4,5 York et al demonstrated that β-glucuronidase (hGUS), a homotetrameric lysosomal enzyme bearing multiple M6P moieties, stabilized the receptor's dimeric structure by cross-bridging the M6P binding sites on two adjacent subunits. 5 These data support a dimeric model for binding of bivalent M6P-based ligands by the M6P/IGF2R (Figure 1). Importantly, they also observed that hGUS binding increased the rate of internalization of the receptor and consequently stimulated the degradation of any passenger ligands, including IGF-II, by 3-to 4-fold.…”

mentioning

confidence: 99%

“…A tripeptide version of this compound bound the M6P/IGF2R with high affinity, which led to the hypothesis of a bivalent M6P-based mechanism. 5,11 However, upon closer inspection, it appears that the exceptional binding affinity of this compound was attributable to an anthranoyl group present on the lysine ε-amino group within the core peptide ( Figure 3). This modification increased the affinity by ~200-fold relative to the same compound with an unmodified peptide, 11 presumably through interaction with a hydrophobic patch on the receptor proximal to the M6P binding site.…”

mentioning

confidence: 99%

See 3 more Smart Citations

A set of phosphatase-inert “molecular rulers” to probe for bivalent mannose 6-phosphate ligand–receptor interactions

Fei

Connelly

MacDonald

et al. 2008

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

A set of bivalent mannose 6-phosphonate "molecular rulers" has been synthesized to examine ligand binding to the M6P/IGF2R. The set is estimated to span a P-P distance range of 16-26 Å (MMFF energy minimization on the hydrated phosphonates). Key synthetic transformations include sugar triflate displacement for phosphonate installation and Grubbs I cross-metathesis to achieve bivalency. Relative binding affinities were tested by radioligand displacement assays versus PMP-BSA (pentamannose phosphate-bovine serum albumin). These compounds exhibit slightly higher binding affinities for the receptor (IC 50 's = 3.7-5 μM) than the parent, monomeric mannose 6-phosphonate ligand and M6P itself (IC 50 = 11.5 ± 2.5 μM). These results suggest that the use of an α-configured anomeric alkane tether is acceptable, as no significant thermodynamic penalty is apparently paid with this design. On the other hand, the modest gains in binding affinity observed suggest that this ligand set has not yet found true bivalent interaction with the M6P/IGF2R (i.e. binding to two distinct M6P-binding pockets).The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is a type I transmembrane glycoprotein that cycles through the Golgi, endosomes, and the plasma membrane to carry out its role in the transport of lysosomal enzymes to their cellular destination. 1 The receptor also functions in the binding, uptake, and degradation of the mitogen, insulin-like growth factor II (IGF-II) and facilitates activation of the growth inhibitor, transforming growth factor-β. The ability of the M6P/IGF2R to inhibit cell proliferation, or stimulate apoptosis, by these mechanisms has implicated the receptor as a tumor suppressor. The IGF-II binding activity of the M6P/IGF2R is mainly responsible for its growth suppressor function. Many cancers become growth factor-independent by high-level expression of IGF-II, which not only binds to the M6P/IGF2R, but also to the IGF1R. The high affinity interaction of IGF-II with the IGF1R leads to activation of IGF1R signaling pathways that promote cell division and survival.2 § Note: These authors contributed equally to this work. Supplementary dataExperimental procedures, spectral data, copies of NMR spectra and details of the radioligand displacement assays can be found in the online version at ____.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Figure 1). Importantly, they also observed that hGUS binding increased the rate of internalization of the receptor and consequently stimulated the degradation of any passenger ligands, including IGF-II, by 3...

show abstract

mentioning

confidence: 97%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

A set of phosphatase-inert “molecular rulers” to probe for bivalent mannose 6-phosphate ligand–receptor interactions

Fei

Connelly

MacDonald

et al. 2008

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

show abstract

“…IGF2R is known to mediate delivery of proteins to the lysosome. [5][6][7] Oxyrane used the yeasts Yarrowia lipolytica and Pichia pastoris to produce modified GAA. In prior work, Oxyrane researchers and colleagues had engineered those yeast to yield much higher levels of carbohydrate modifications than the mammalian cell lines used to produce Myozyme and Lumizyme.…”

mentioning

confidence: 99%

Muscling up on Myozyme

Fulmer¹

2012

Science-Business eXchange

View full text Add to dashboard Cite

P‐Type Lectins and Lysosomal Enzyme Trafficking

Marron-Terada¹,

Dahms²,

Ernst

et al. 2000

Carbohydrates in Chemistry and Biology

Self Cite

View full text Add to dashboard Cite

The P-type lectins derived their name from their ability to bind phosphorylated mannose residues. There are only two members of this lectin family: the 300 kDa cation-independent mannose 6-phosphate receptor (CI-MPR) and the 46 kDa cation-dependent mannose 6-phosphate receptor (CD-MPR), both of which are involved in targeting newly synthesized soluble acid hydrolases to the lysosome. Lysosomal enzymes acquire mannose 6-phosphate (Man-6-P) residues on their Nlinked oligosaccharides which function as a recognition marker for the MPRs. The MPRs are found ubiquitously in higher eukaryotes, and most cell types express both receptors. The CI-MPR is often referred to as the mannose 6-phosphate/ insulin-like growth factor 11 receptor to reflect the bifunctional nature of the mammalian receptor which is capable of binding Man-6-P-containing ligands as well as the polypeptide hormone, insulin-like growth factor I1 (IGF-11). However, recent studies showing that the CI-MPR binds two other ligands, retinoic acid [ 11 and the urokinase-type plasminogen activator receptor [2], demonstrate that the CI-MPR is truly a multifunctional receptor capable of recognizing a number of different ligands via distinct binding sites.In addition to soluble lysosomal enzymes, Man-6-P residues have been identified on a number of other proteins, including epidermal growth factor receptor, Herpes simplex virus glycoprotein D, thyroglobulin, transforming growth factor-p precursor, proliferin, leukemia inhibitory factor, and DNase I. The ability of these proteins to be recognized by the MPRs suggests that the receptors are involved in a number of diverse cellular events due to their carbohydrate binding activities. This Chapter will focus on the carbohydrate binding specificities of the MPRs and will summarize the information gained from the recent crystal structure of the CD-MPR which has provided the first look at the carbohydrate-recognition domain (CRD) of this lectin family. The reader is referred to reviews [3, 41 for a more complete summary of earlier work on the biosynthesis and intracellular trafficking of the MPRs and lysosomal enzymes. Carbohydrates in Chemistry and Biology

show abstract

The Rate of Internalization of the Mannose 6-Phosphate/Insulin-like Growth Factor II Receptor Is Enhanced by Multivalent Ligand Binding

Cited by 105 publications

References 47 publications

A set of phosphatase-inert “molecular rulers” to probe for bivalent mannose 6-phosphate ligand–receptor interactions

A set of phosphatase-inert “molecular rulers” to probe for bivalent mannose 6-phosphate ligand–receptor interactions

Muscling up on Myozyme

P‐Type Lectins and Lysosomal Enzyme Trafficking

Contact Info

Product

Resources

About