Heparan sulfate proteoglycans at a glance

Kirkpatrick, Catherine; Selleck, Scott B.

doi:10.1242/jcs.03432

Cited by 101 publications

(92 citation statements)

References 69 publications

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“…We then tested whether this activity is mediated by secreted factors or by angiogenin in particular. Angiogenin has been characterized as a heparin-binding protein and is likely to require heparan sulfate proteoglycans to mediate uptake into astrocytes, a mechanism known to be involved in the uptake of other angiogenic molecules such as basic fibroblast growth factor/fibroblast growth factor-2 (bFGF/ FGF-2) and vascular endothelial growth factor (VEGF; Soncin et al, 1997;Kirkpatrick and Selleck, 2007). To determine whether constitutive RNA cleavage of mixed primary motoneuron cultures was caused by a paracrine factor consistent with this mechanism, we applied heparin (1 g/ ml) to the culture medium and observed a strong inhibition of RNA cleavage (Fig.…”

Section: Angiogenin Mediates Stress-induced Rna Cleavage In Astrocytesmentioning

confidence: 99%

“…Cell surface heparan sulfate proteoglycans are contained within either the syndecans, which contain a single transmembrane domain, or the glypicans, which are tethered to the plasma membrane with a glycosylphosphatidylinositol anchor (Kirkpatrick and Selleck, 2007). Although these receptors lack catalytic activity, syndecan 4 is unique in being capable of binding phosphatidylinositol (4,5)-P2, therefore independently initiating signaling via Rac1, protein kinase C␣, PI3K, Cdc42, mTORC2, and Akt (Ilan et al, 1998;Simons and Horowitz, 2001;Tkachenko et al, 2004;Partovian et al, 2008).…”

Section: The Receptor For Angiogenin Uptake Into Astrocytes Is Syndecmentioning

confidence: 99%

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Motoneurons Secrete Angiogenin to Induce RNA Cleavage in Astroglia

Skorupa

King²,

Aparicio³

et al. 2012

J. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder affecting motoneurons. Mutations in angiogenin, encoding a member of the pancreatic RNase A superfamily, segregate with ALS. We previously demonstrated that angiogenin administration shows promise as a neuroprotective therapeutic in studies using transgenic ALS mice and primary motoneuron cultures. Its mechanism of action and target cells in the spinal cord, however, are largely unknown. Using mixed motoneuron cultures, motoneuron-like NSC34 cells, and primary astroglia cultures as model systems, we here demonstrate that angiogenin is a neuronally secreted factor that is endocytosed by astroglia and mediates neuroprotection in paracrine. We show that wild-type angiogenin acts unidirectionally to induce RNA cleavage in astroglia, while the ALS-associated K40I mutant is also secreted and endocytosed, but fails to induce RNA cleavage. Angiogenin uptake into astroglia requires heparan sulfate proteoglycans, and engages clathrin-mediated endocytosis. We show that this uptake mechanism exists for mouse and human angiogenin, and delivers a functional RNase output. Moreover, we identify syndecan 4 as the angiogenin receptor mediating the selective uptake of angiogenin into astroglia. Our data provide new insights into the paracrine activities of angiogenin in the nervous system, and further highlight the critical role of non-neuronal cells in the pathogenesis of ALS.

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Section: Angiogenin Mediates Stress-induced Rna Cleavage In Astrocytesmentioning

confidence: 99%

Section: The Receptor For Angiogenin Uptake Into Astrocytes Is Syndecmentioning

confidence: 99%

Motoneurons Secrete Angiogenin to Induce RNA Cleavage in Astroglia

Skorupa

King²,

Aparicio³

et al. 2012

J. Neurosci.

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“…The function of heparan sulfate proteoglycans (HSPGs) has been the subject of intense investigation in the last decade, and it is now clear they play essential roles in development, controlling both responses of cells to secreted growth factors, as well as the distribution of growth factors in the matrix (Lin, 2004;Bülow and Hobert, 2006;Kirkpatrick and Selleck, 2007). HSPGs are also critical for nervous system development, affecting such diverse events as axon guidance and the localization of synaptic components (Hoch et al, 1994;Yamaguchi, 2002;Lee et al, 2004;Rotundo et al, 2005;Jenniskens et al, 2006;Lindwall et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Cell Type-Specific Requirements for Heparan Sulfate Biosynthesis at the Drosophila Neuromuscular Junction: Effects on Synapse Function, Membrane Trafficking, and Mitochondrial Localization

Ren¹,

Kirkpatrick²,

Rawson³

et al. 2009

Journal of Neuroscience

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Heparan sulfate proteoglycans (HSPGs) are concentrated at neuromuscular synapses in many species, including Drosophila. We have established the physiological and patterning functions of HSPGs at the Drosophila neuromuscular junction by using mutations that block heparan sulfate synthesis or sulfation to compromise HSPG function. The mutant animals showed defects in synaptic physiology and morphology suggesting that HSPGs function both presynaptically and postsynaptically; these defects could be rescued by appropriate transgene expression. Of particular interest were selective disruptions of mitochondrial localization, abnormal distributions of Golgi and endoplasmic reticulum markers in the muscle, and a markedly increased level of stimulus-dependent endocytosis in the motoneuron. Our data support the emerging view that HSPG functions are not limited to the cell surface and matrix environments, but also affect a diverse set of cellular processes including membrane trafficking and organelle distributions.

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“…In addition to BMPs, HSPGs serve as co-receptors for a number of other growth factors and morphogens, including FGF, WNT, and Hedgehog (4). HSPGs generally are thought to regulate growth factor signaling on the surface of the signal-receiving cells (5).…”

mentioning

confidence: 99%

Novel Contact-dependent Bone Morphogenetic Protein (BMP) Signaling Mediated by Heparan Sulfate Proteoglycans

Dejima

Kanai

Akiyama

et al. 2011

Journal of Biological Chemistry

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We previously proposed a model that DALLY, a Drosophila glypican, acts as a trans co-receptor to regulate BMP signaling in the germ line stem cell niche. To investigate the molecular mechanisms of contact-dependent BMP signaling, we developed novel in vitro assay systems to monitor trans signaling using Drosophila S2 cells. Using immunoblot-based as well as single-cell assay systems, we present evidence that Drosophila glypicans indeed enhance BMP signaling in trans in a contactdependent manner in vitro. Our analysis showed that heparan sulfate modification is required for the trans co-receptor activity of DALLY. Two BMP-like molecules, Decapentaplegic (DPP) and Glass bottom boat, can mediate trans signaling through a heparan sulfate proteoglycan co-receptor in S2 cells. The in vitro systems reflect the molecular characteristics of heparan sulfate proteoglycan functions observed previously in vivo, such as ligand specificity and biphasic activity dependent on the ligand dosage. In addition, experiments using a DALLY-coated surface suggested that DALLY regulates DPP signaling in trans by its effect on the stability of DPP protein on the surface of the contacting cells. Our findings provide the molecular foundation for novel contact-dependent signaling, which defines the physical space of the stem cell niche in vivo. Bone morphogenetic proteins (BMPs)2 play critical roles in cell-cell communication during animal development. Remarkably, these molecules mediate both long and short range signaling dependent on context. For example, Decapentaplegic (DPP), a Drosophila homologue of BMPs, acts as a long range morphogen in the developing wing and as a contact-dependent niche factor in the female germ line stem cell (GSC) niche. The molecular basis underlying this differential activity of BMPs is not fully understood.Signaling and distribution of BMPs in a tissue are modulated by a class of carbohydrate-modified molecules, heparan sulfate proteoglycans (HSPGs) (1-3). In addition to BMPs, HSPGs serve as co-receptors for a number of other growth factors and morphogens, including FGF, WNT, and Hedgehog (4). HSPGs generally are thought to regulate growth factor signaling on the surface of the signal-receiving cells (5). It has been reported, however, that HSPGs can regulate signaling in trans from neighboring cells in some cases (6, 7).Recent studies demonstrated that HSPGs are essential regulators of the GSC niche in the Drosophila ovary (8, 9). Although it has been well established that DPP regulates the asymmetric division of a GSC (10), the mechanism by which this secreted molecule differentially regulates two daughter cells has been a mystery. We have found previously that DALLY, a Drosophila HSPG of the glypican type, is expressed specifically in the somatic niche cells (the cap cells) contacting GSCs and is required for GSC maintenance (8). Ectopic dally expression in somatic cells in a wide region of the germarium was sufficient to maintain all the contacting germ line cells as GSC-like undifferentiated cells, thus e...

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Heparan sulfate proteoglycans at a glance

Cited by 101 publications

References 69 publications

Motoneurons Secrete Angiogenin to Induce RNA Cleavage in Astroglia

Motoneurons Secrete Angiogenin to Induce RNA Cleavage in Astroglia

Cell Type-Specific Requirements for Heparan Sulfate Biosynthesis at the Drosophila Neuromuscular Junction: Effects on Synapse Function, Membrane Trafficking, and Mitochondrial Localization

Novel Contact-dependent Bone Morphogenetic Protein (BMP) Signaling Mediated by Heparan Sulfate Proteoglycans

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