A Single Receptor Binds Both Insulin-Like Growth Factor II and Mannose-6-Phosphate

MacDonald, Richard G.; Pfeffer, Suzanne R.; Coussens, Lisa M.; Tepper, Mark A.; Brocklebank, Carol M.; Mole, John E.; Anderson, John; Chen, Ellson; Czech, Michael P.; Ullrich, Axel

doi:10.1126/science.2964083

Cited by 355 publications

(131 citation statements)

References 53 publications

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“…Type II IGF Receptor The type II IGF receptor (IGF-IIR) or the cationindependent mannose-6-phosphate receptor (24) binds IGF-II but lacks tyrosine kinase activity and does not transduce signals (24). It binds IGF-II, among other proteins, and seems to serve as a sink for IGF-II.…”

Section: Insulin Receptormentioning

confidence: 99%

Disrupting insulin-like growth factor signaling as a potential cancer therapy

Sachdev

Yee

2007

Molecular Cancer Therapeutics

327

182

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Section: Insulin Receptormentioning

confidence: 99%

Disrupting insulin-like growth factor signaling as a potential cancer therapy

Sachdev

Yee

2007

Molecular Cancer Therapeutics

327

182

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“…[1][2][3][4][5][6] The receptor is widely expressed in various tissues including the brain and recognizes, via distinct sites, two different classes of ligands: M6P-containing molecules such as lysosomal enzymes, and IGF-II, a mitogenic polypeptide with structural homology to IGF-I and insulin. 2,7,8 A subpopulation of the CI-MPR is located at the plasma membrane, where it regulates internalization of IGF-II and various exogenous M6P-containing ligands for subsequent clearance or activation. However, the majority of the receptors are expressed in the trans-Golgi network/endosomal compartments and are involved in the intracellular trafficking of a battery of lysosomal enzymes including cathepsins B and D. 1,2,5,9,10 Given the evidence that defects in the synthesis/targeting of lysosomal enzymes or dysfunction of the endosomal-lysosomal (EL) system are associated with a variety of neurodegenerative disorders, often with progressive cognitive decline, [11][12][13][14] it is possible that the CI-MPR may have a role in regulating neuronal viability.…”

mentioning

confidence: 99%

Up-Regulation of Cation-Independent Mannose 6-Phosphate Receptor and Endosomal-Lysosomal Markers in Surviving Neurons after 192-IgG-Saporin Administrations into the Adult Rat Brain

Hawkes

Kabogo

Amritraj

et al. 2006

The American Journal of Pathology

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The cation-independent mannose 6-phosphate receptor (CI-MPR) is a single transmembrane domain glycoprotein that plays a major role in the trafficking of lysosomal enzymes from the trans-Golgi network to the endosomal-lysosomal (EL) system. Because dysfunction of EL system is associated with a variety of neurodegenerative disorders, it is possible that the CI-MPR may have a role in regulating neuronal viability after toxicity/injury. In the present study, we report that 192-IgG-saporin-induced loss of basal forebrain cholinergic neurons causes a transient upregulation of CI-MPR protein levels in surviving neurons of the basal forebrain and frontal cortex but not in the brainstem region, which was relatively spared by the immunotoxin. This was accompanied by a parallel time-dependent increase in other EL markers, ie, cathepsin D, Rab5, and LAMP2 in the basal forebrain region, whereas in the frontal cortex the levels of cathepsin D, and to some extent Rab5, were increased. Given the critical role of the EL system in the clearance of abnormal proteins in response to changing conditions, it is likely that the observed increase in the CI-MPR and components of the EL system in surviving neurons after 192-IgG-saporin treatment represents an adaptive mechanism to restore the metabolic/structural abnormalities induced by the loss of cholinergic neurons.

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“…We hypothesized that a portion of IGF-II (hereafter referred to as the ''GILT tag'') retaining the ability to bind to the IGF-II͞CI-MPR would serve as an effective targeting moiety when fused to lysosomal enzymes. Such a GILT-tagged protein would target the identical receptor targeted by Man6-P (albeit to a distinct binding site), thereby sharing the identical endocytic pathway for lysosomal targeting with Man6-Pcontaining proteins (22)(23)(24)(25)(26)(27).…”

mentioning

confidence: 99%

Glycosylation-independent targeting enhances enzyme delivery to lysosomes and decreases storage in mucopolysaccharidosis type VII mice

LeBowitz

Grubb

Maga

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Enzyme-replacement therapy is an established means of treating lysosomal storage diseases. Infused therapeutic enzymes are targeted to lysosomes of affected cells by interactions with cellsurface receptors that recognize carbohydrate moieties, such as mannose and mannose 6-phosphate, on the enzymes. We have tested an alternative, peptide-based targeting system for delivery of enzymes to lysosomes in a murine mucopolysaccharidosis type VII (MPS VII) model. This strategy depends on the interaction of a fragment of insulin-like growth factor II (IGF-II), with the IGF-II binding site on the bifunctional, IGF-II cation-independent mannose 6-phosphate receptor. A chimeric protein containing a portion of mature human IGF-II fused to the C terminus of human ␤-glucuronidase was taken up by MPS VII fibroblasts in a mannose 6-phosphate-independent manner, and its uptake was inhibited by the addition of IGF-II. Furthermore, the tagged enzyme was delivered effectively to clinically significant tissues in MPS VII mice and was effective in reversing the storage pathology. The tagged enzyme was able to reduce storage in glomerular podocytes and osteoblasts at a dose at which untagged enzyme was much less effective. This peptide-based, glycosylation-independent lysosomal targeting system may enhance enzyme-replacement therapy for certain human lysosomal storage diseases.␤-glucuronidase ͉ IGF-II͞Man6-P receptor ͉ receptor-mediated endocytosis ͉ enzyme-replacement therapy ͉ lysosomal storage disease

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A Single Receptor Binds Both Insulin-Like Growth Factor II and Mannose-6-Phosphate

Cited by 355 publications

References 53 publications

Disrupting insulin-like growth factor signaling as a potential cancer therapy

Disrupting insulin-like growth factor signaling as a potential cancer therapy

Up-Regulation of Cation-Independent Mannose 6-Phosphate Receptor and Endosomal-Lysosomal Markers in Surviving Neurons after 192-IgG-Saporin Administrations into the Adult Rat Brain

Glycosylation-independent targeting enhances enzyme delivery to lysosomes and decreases storage in mucopolysaccharidosis type VII mice

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