Soluble Insulin-like Growth Factor II/Mannose 6-Phosphate Receptor Carries Multiple High Molecular Weight Forms of Insulin-like Growth Factor II in Fetal Bovine Serum

Valenzano, Kenneth J.; Remmler, Jill; Lobel, Peter

doi:10.1074/jbc.270.27.16441

Cited by 53 publications

(42 citation statements)

References 41 publications

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“…In agreement with our observations, a proIGF-II-immunoreactivity has been detected in human AF (Liu et al 1993). At least 12 different forms of high M r IGF-II molecules, with a similar protein backbone of 87 amino acid and different amounts of sialylated, O-linked sugars linked to the E-peptide extension, were identified by Valenzano et al (1995) and Valenzano et al (1997) in foetal bovine serum. Other IGF-II isoforms with high M r are produced by alternative splicing (Jansen et al 1985) and by processing at Arg 104 (Duguay et al 1998).…”

Section: Discussionsupporting

confidence: 76%

Mitogenic activity of high molecular weight forms of insulin-like growth factor-II in amniotic fluid

Blahovec

Kostecká²,

Lacroix³

et al. 2001

Journal of Endocrinology

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Amniotic fluid (AF) collected from ewes and goats at mid gestation displayed mitogenic activity in mouse fibroblasts. Upon fractionation of this material by size exclusion chromatography, the mitogenic activity was resolved into two peaks, whose activity was inhibited by an anti-IGF type 1 receptor blocking antibody. One of the peaks contained IGF-I and IGF-II (mature form), whereas the other contained high M r precursor forms of IGF-II. The presence in this latter fraction of IGF-binding proteins (IGFBP) suggests that the AF IGFBPs do not efficiently inhibit the mitogenic activity of the high M r forms of IGF-II. In agreement with this conclusion, exogenous IGFBP-1 failed to affect this activity. Analysis of IGF-II in sheep AF showed that the AF concentrations of both forms of IGF-II increased dramatically from mid pregnancy until 106-120 days of gestation, and fell thereafter. The amniotic IGFBPs followed a similar evolution. High M r forms of IGF-II were also found in human AF, with a pattern of electrophoretic migration different from that of sheep. We suggest that the precursor forms of IGF-II may play an important role in foetal development.

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Section: Discussionsupporting

confidence: 76%

Mitogenic activity of high molecular weight forms of insulin-like growth factor-II in amniotic fluid

Blahovec

Kostecká²,

Lacroix³

et al. 2001

Journal of Endocrinology

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“…In the presence of labelled IGF-II, very high molecular mass binding (>140 kDa) was also demonstrated. This was not present when IGF-I was used as the ligand, raising the possibility that this represents a soluble form of the IGF-II/mannose 6-phosphate receptor, which has been detected in human serum and urine (Kiess et al 1987, Causin et al 1988, Gelato et al 1988, Valenzano et al 1995. The serum IGF-II/mannose 6-phosphate receptor increases in pregnant diabetic women (Gelato et al 1993) and is stimulated by insulin injection in rats (Clairmont & Czech 1990).…”

Section: Discussionmentioning

confidence: 99%

Regulation of insulin-like growth factor-binding protein-3 ternary complex in feline diabetes mellitus

Lewitt

Hazel²,

Church³

et al. 2000

Journal of Endocrinology

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The 140 kDa ternary complex of insulin-like growth factor-binding protein-3 (IGFBP-3), IGFs and an acidlabile subunit (ALS) has previously been shown to be decreased in diabetes mellitus in humans and rats. We have studied IGF-I levels and ternary complex formation in normal and diabetic cats. Total IGF-I concentrations, measured by RIA using des(1-3)-IGF-I as tracer were ( ...) 54 13 nmol/l in eight normal and 227 57 nmol/l in eight diabetic cats (P<0·01). The size-distribution of IGFBPs in the cat circulation was determined by incubation with 125 I-IGF-II and Superose 12 chromatography. In normal animals 26 2% of the 125 I-IGF-II were in a 140 kDa form compared with 48 5% in diabetic cats (P<0·01). When samples from normal and diabetic animals were co-incubated 52 3% were at 140 kDa. A similar shift was seen when normal cat and normal human serum were co-incubated. A 2-fold increase in the 140 kDa form in diabetic cats was confirmed first by size-fractionating samples and then performing a ligand-binding assay with 125 I-IGF-I or -II and charcoal separation. SDS-PAGE and Western ligand blotting demonstrated a 45 kDa doublet (presumably IGFBP-3) and 30-35 kDa forms. There were no apparent differences between normal and diabetic profiles on SDS-PAGE, suggesting that a proportion of IGFBP-3 which circulates 'free' in normal cats forms a ternary complex in the diabetic circulation. We conclude that (i) in contrast to humans and rats, ALS is the limiting factor for ternary complex formation in normal cats, (ii) ALS concentrations increase in feline diabetes mellitus and, by promoting ternary complex formation, this leads to an increase in total IGF-I concentrations, and (iii) total IGF-I concentrations may not be reliable in the diagnosis of acromegaly in diabetic cats.

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“…CI-MPR Affinity Chromatography and Enzyme Assays-Soluble bovine CI-MPR was purified from FBS and covalently conjugated to cyanogen bromide-activated Sepharose 4B (Sigma) at 1 mg/ml as described (19). Two days post-transfection, HeLa cells in a 6-well plate were collected and lysed with 250 l of cell lysis buffer (25 mM Tris-Cl, pH 7.2, 150 mM NaCl, 1% Triton X-100) containing protease inhibitors.…”

Section: Methodsmentioning

confidence: 99%

Multiple Domains of GlcNAc-1-phosphotransferase Mediate Recognition of Lysosomal Enzymes

Meel¹,

Lee²,

Liu³

et al. 2016

Journal of Biological Chemistry

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The Golgi enzyme UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase), an ␣ 2 ␤ 2 ␥ 2 hexamer, mediates the initial step in the addition of the mannose 6-phosphate targeting signal on newly synthesized lysosomal enzymes. This tag serves to direct the lysosomal enzymes to lysosomes. A key property of GlcNAc-1-phosphotransferase is its unique ability to distinguish the 60 or so lysosomal enzymes from the numerous nonlysosomal glycoproteins with identical Asn-linked glycans. In this study, we demonstrate that the two Notch repeat modules and the DNA methyltransferase-associated protein interaction domain of the ␣ subunit are key components of this recognition process. Importantly, different combinations of these domains are involved in binding to individual lysosomal enzymes. This study also identifies the ␥-binding site on the ␣ subunit and demonstrates that in the majority of instances the mannose 6-phosphate receptor homology domain of the ␥ subunit is required for optimal phosphorylation. These findings serve to explain how GlcNAc-1-phosphotransferase recognizes a large number of proteins that lack a common structural motif.Correct targeting of newly synthesized acid hydrolases to lysosomes is essential for this organelle to maintain its function of degrading intracellular and endocytosed material. In higher eukaryotes, this process is mediated by the mannose 6-phosphate (Man-6-P) 5 recognition system whereby the newly synthesized acid hydrolases acquire Man-6-P residues in the Golgi that serve as high affinity ligands for binding to Man-6-P receptors (MPRs) in the trans-Golgi network and subsequent transport to the endo-lysosomal system (1). The initial and most critical step in the generation of the Man-6-P tag is mediated by the Golgi enzyme UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase). This enzyme binds selectively to conformation-dependent protein determinants in the 60 or so lysosomal acid hydrolases and transfers GlcNAc-1-P from UDP-GlcNAc to mannose residues on high mannose-type N-linked glycans of the hydrolases (2). The GlcNAc is subsequently excised by a second Golgi enzyme ("uncovering enzyme") to generate the high affinity Man-6-P ligand (3).GlcNAc-1-phosphotransferase is an ␣ 2 ␤ 2 ␥ 2 hexamer that is encoded by two genes (4 -7). The GNPTAB gene encodes the ␣ and ␤ subunits, whereas the GNPTG gene encodes the ␥ subunit. Enzyme kinetic studies have indicated that the ␣ and ␤ subunits specifically bind lysosomal acid hydrolases and mediate the catalytic function of the enzyme (8, 9). The ␥ subunit enhances the rate of GlcNAc-P transfer to a subset of the acid hydrolases without substantially altering the binding to these acceptors. Consistent with this, analysis of the level of mannose phosphorylation of the acid hydrolases in the brain of mice lacking the ␥ subunit, as estimated by the extent of binding to a cation-independent (CI)-MPR affinity resin, indicated that about one-third of the acid hydrol...

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Soluble Insulin-like Growth Factor II/Mannose 6-Phosphate Receptor Carries Multiple High Molecular Weight Forms of Insulin-like Growth Factor II in Fetal Bovine Serum

Cited by 53 publications

References 41 publications

Mitogenic activity of high molecular weight forms of insulin-like growth factor-II in amniotic fluid

Mitogenic activity of high molecular weight forms of insulin-like growth factor-II in amniotic fluid

Regulation of insulin-like growth factor-binding protein-3 ternary complex in feline diabetes mellitus

Multiple Domains of GlcNAc-1-phosphotransferase Mediate Recognition of Lysosomal Enzymes

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