Serglycin proteoglycan: Regulating the storage and activities of hematopoietic proteases

Pejler, Gunnar; Åbrink, Magnus; Wernersson, Sara

doi:10.1002/biof.11

Cited by 50 publications

(65 citation statements)

References 57 publications

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“…SRGN (serglycin) is a proteoglycan critical for maintaining storage of secretory granule proteases. More interestingly, proteoglycans have been implicated as modulators of axonal growth and plasticity via their chondroitin sulfate chains, a function regulated by both BDNF and glucocorticoids in the brain (55,56).…”

Section: Figmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor Signaling Rewrites the Glucocorticoid Transcriptome via Glucocorticoid Receptor Phosphorylation

Lambert

Neubert

et al. 2013

Molecular and Cellular Biology

106

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Abnormal glucocorticoid and neurotrophin signaling has been implicated in numerous psychiatric disorders. However, the impact of neurotrophic signaling on glucocorticoid receptor (GR)-dependent gene expression is not understood. We therefore examined the impact of brain-derived neurotrophic factor (BDNF) signaling on GR transcriptional regulatory function by gene expression profiling in primary rat cortical neurons stimulated with the selective GR agonist dexamethasone (Dex) and BDNF, alone or in combination. Simultaneous treatment with BDNF and Dex elicited a unique set of GR-responsive genes associated with neuronal growth and differentiation and also enhanced the induction of a large number of Dex-sensitive genes. BDNF via its receptor TrkB enhanced the transcriptional activity of a synthetic GR reporter, suggesting a direct effect of BDNF signaling on GR function. Indeed, BDNF treatment induces the phosphorylation of GR at serine 155 (S155) and serine 287 (S287). Expression of a nonphosphorylatable mutant (GR S155A/S287A) impaired the induction of a subset of BDNF-and Dex-regulated genes. Mechanistically, BDNF-induced GR phosphorylation increased GR occupancy and cofactor recruitment at the promoter of a BDNF-enhanced gene. GR phosphorylation in vivo is sensitive to changes in the levels of BDNF and TrkB as well as stress. Therefore, BDNF signaling specifies and amplifies the GR transcriptome through a coordinated GR phosphorylation-dependent detection mechanism.

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Section: Figmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor Signaling Rewrites the Glucocorticoid Transcriptome via Glucocorticoid Receptor Phosphorylation

Lambert

Neubert

et al. 2013

Molecular and Cellular Biology

106

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“…Serglycin is a proteoglycan consisting of a core protein to which negatively charged glycoaminoglycan (GAG) chains of either chondroitin sulfate or heparin are attached (7,8). The core protein containing 158 amino acid residues can be divided into 3 domains: a signal peptide domain, an N-terminal domain with unknown function, and a C-terminal domain (9).…”

Section: Introductionmentioning

confidence: 99%

“…The core protein containing 158 amino acid residues can be divided into 3 domains: a signal peptide domain, an N-terminal domain with unknown function, and a C-terminal domain (9). The functions of serglycin in various cells depend on the type and size of the GAG chains decorating the core protein (8,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Serglycin Is a Theranostic Target in Nasopharyngeal Carcinoma that Promotes Metastasis

et al. 2011

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Nasopharyngeal carcinoma (NPC) is known for its high-metastatic potential. Here we report the identification of the proteoglycan serglycin as a functionally significant regulator of metastasis in this setting. Comparative genomic expression profiling of NPC cell line clones with high-and low-metastatic potential revealed the serglycin gene (SRGN) as one of the most upregulated genes in highly metastatic cells. RNAi-mediated inhibition of serglycin expression blocked serglycin secretion and the invasive motility of highly metastatic cells, reducing metastatic capacity in vivo. Conversely, serglycin overexpression in poorly metastatic cells increased their motile behavior and metastatic capacity in vivo. Growth rate was not influenced by serglycin in either highly or poorly metastatic cells. Secreted but not bacterial recombinant serglycin promoted motile behavior, suggesting a critical role for glycosylation in serglycin activity. Serglycin inhibition was associated with reduced expression of vimentin but not other epithelial-mesenchymal transition proteins. In clinical specimens, serglycin expression was elevated significantly in liver metastases from NPC relative to primary NPC tumors. We evaluated the prognostic value of serglycin by immunohistochemical staining of tissue microarrays from 263 NPC patients followed by multivariate analyses. High serglycin expression in primary NPC was found to be an unfavorable independent indicator of distant metastasis-free and disease-free survival. Our findings establish that glycosylated serglycin regulates NPC metastasis via autocrine and paracrine routes, and that it serves as an independent prognostic indicator of metastasis-free survival and disease-free survival in NPC patients. Cancer Res; 71(8); 3162-72. Ó2011 AACR.

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“…The storage and activities of MC proteases are, to a large extent, influenced by serglycin (Pejler et al , 2009a ;Kolset and Pejler , 2011 ), a proteoglycan species composed of a small protein core to which strongly negatively charged side chains of heparin (or chondroitin sulfate) type are attached. Primarily, serglycin proteoglycans are known to serve as storage matrices for several of the MC proteases, including mMCP-4, mMCP-5, mMCP-6 and MC-CPA, as shown by the absence of these proteases in MCs from serglycin-deficient mice ( Å brink et al, 2004 ).…”

Section: Introductionmentioning

confidence: 99%

Mast cells limit extracellular levels of IL-13 via a serglycin proteoglycan-serine protease axis

Waern

Karlsson

Thorpe

et al. 2012

Biological Chemistry

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: Mast cell (MC) granules contain large amounts of proteases of the chymase, tryptase and carboxypeptidase A (MC-CPA) type that are stored in complex with serglycin, a proteoglycan with heparin side chains. Hence, serglycinprotease complexes are released upon MC degranulation and may influence local inflammation. Here we explored the possibility that a serglycin-protease axis may regulate levels of IL-13, a cytokine involved in allergic asthma. Indeed, we found that wild-type MCs efficiently degraded exogenous or endogenously produced IL-13 upon degranulation, whereas serglycin −/− MCs completely lacked this ability. Moreover, MC-mediated IL-13 degradation was blocked both by a serine protease inhibitor and by a heparin antagonist, which suggests that IL-13 degradation is catalyzed by serglycin-dependent serine proteases and that optimal IL-13 degradation is dependent on both the serglycin and the protease component of the serglycin-protease complex. Moreover, IL-13 degradation was abrogated in MC-CPA −/− MC cultures, but was normal in cultures of MCs with an inactivating mutation of MC-CPA, which suggests that the IL-13-degrading serine proteases rely on MC-CPA protein. Together, our data implicate a serglycin-serine protease axis in the regulation of extracellular levels of IL-13. Reduction of IL-13 levels through this mechanism possibly can provide a protective function in the context of allergic inflammation.

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Serglycin proteoglycan: Regulating the storage and activities of hematopoietic proteases

Cited by 50 publications

References 57 publications

Brain-Derived Neurotrophic Factor Signaling Rewrites the Glucocorticoid Transcriptome via Glucocorticoid Receptor Phosphorylation

Brain-Derived Neurotrophic Factor Signaling Rewrites the Glucocorticoid Transcriptome via Glucocorticoid Receptor Phosphorylation

Serglycin Is a Theranostic Target in Nasopharyngeal Carcinoma that Promotes Metastasis

Mast cells limit extracellular levels of IL-13 via a serglycin proteoglycan-serine protease axis

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