Chromogranin A processing and secretion: specific role of endogenous and exogenous prohormone convertases in the regulated secretory pathway.

Eskeland, N L; Zhou, An; Dinh, Thai; Wu, Hongjiang; Parmer, Robert J.; Mains, Richard E.; O’Connor, Daniel T.

doi:10.1172/jci118760

Cited by 103 publications

(73 citation statements)

References 55 publications

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“…AtT-20 cells contain both the regulated and constitutive secretory pathways and have been used extensively to study protein processing and sorting (25,26,(33)(34)(35)(36). Sorting of BDNF, NGF, and NT-3 in AtT-20 cells is identical to that observed in hippocampal neurons in culture (2,3), suggesting that AtT-20 cells are a good model for studying the processing of secretory proteins in neurons.…”

Section: Discussionmentioning

confidence: 99%

Neurotrophin-4, Alone or Heterodimerized with Brain-derived Neurotrophic Factor, Is Sorted to the Constitutive Secretory Pathway

Hibbert

Morris

Seidah

et al. 2003

Journal of Biological Chemistry

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Nerve growth factor and neurotrophin-3 (NT-3) are processed within the constitutive secretory pathway of neurons and neuroendocrine cells and are released continuously in an activity-independent fashion. In contrast, brain-derived neurotrophic factor (BDNF) is processed in the regulated secretory pathway, stored in vesicles, and released in response to neuronal activity, consistent with its role in modulating synaptic plasticity. In this study, we used vaccinia virus infection and transfection methods to monitor the processing and sorting of neurotrophin-4 (NT-4) in AtT-20 cells, which have been used as a model for the sorting of secretory proteins in neurons. Our data show that NT-4 is processed in the constitutive secretory pathway. The molecule is diffusely distributed within the cells and released, soon after being synthesized, in a manner that is not affected by cell depolarization. We further show that NT-4 and BDNF, when co-expressed, can form heterodimers that are constitutively released. In contrast, heterodimers of NT-3 and BDNF have been shown to be released through the regulated secretory pathway. Thus, NT-4, alone or when co-expressed with BDNF, is processed within and secreted by the constitutive secretory pathway.

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Section: Discussionmentioning

confidence: 99%

Neurotrophin-4, Alone or Heterodimerized with Brain-derived Neurotrophic Factor, Is Sorted to the Constitutive Secretory Pathway

Hibbert

Morris

Seidah

et al. 2003

Journal of Biological Chemistry

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“…Several studies using gene transfer techniques suggest that PC1 and PC2 may be involved in the processing of the granin family (Arden et al 1994;Dittie and Tooze 1995;Hoflehner et al 1995;Eskeland et al 1996;Laslop et al 1998). This view is supported by our previous ICC study demonstrating co-localization of PC1, PC2, and CgA in large lucent secretory granules and co-localization of PC2 and SgII in small dense secretory granules of rat pituitary gonadotrophs (Uehara et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Immunocytochemical Localization of Prohormone Convertases PC1 and PC2 in the Mouse Thyroid Gland and Respiratory Tract

Kurabuchi

Tanaka

2002

J Histochem Cytochem.

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S U M M A R YWe examined immunocytochemical localization of the prohormone convertases, PC1 and PC2, in the thyroid gland and respiratory tract of the adult mouse using the indirect enzyme-and immunogold-labeled antibody methods for light and electron microscopy, respectively. In the thyroid gland, PC1-and/or PC2-immunoreactive cells were cuboidal, scattered in the follicular epithelium and in the interfollicular spaces. When serial sections were immunostained with anti-calcitonin, anti-PC1, anti-calcitonin-gene-relatedpeptide (CGRP), and anti-PC2 sera, respectively, localization of both PC1 and PC2 was restricted to the calcitonin/CGRP-producing parafollicular cells. In the respiratory tract, only PC1 immunoreactivity was observed in the basal granulated neuroendocrine cells, which were scattered in the tracheal epithelium. Consecutive sections immunostained with anti-PC1 and anti-CGRP sera showed that a subpopulation of these PC1-immunoreactive cells contained CGRP. Double immunogold electron microscopy of the thyroid parafollicular cells revealed that calcitonin-and/or CGRP-immunopositive secretory granules were also labeled with both PC1 and PC2. These findings suggest that procalcitonin is proteolytically cleaved by PC2 alone or by PC2 together with PC1, and that the proCGRP is cleaved by PC1.

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“…5 Chromogranins are pro-proteins, with multiple recognition sites for endopeptidases, including the serine endopeptidases, PC1 and PC2. 6 Both CgA and CgB undergo post-translational processing, generating several products ( Figure 1). The antibodies used in assays which measure circulating chromogranins are developed using fragments and not the whole chromogranin molecule.…”

Section: Chromograninsmentioning

confidence: 99%

The biochemical utility of chromogranin A, chromogranin B and cocaine- and amphetamine-regulated transcript for neuroendocrine neoplasia

et al. 2013

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Neuroendocrine neoplasia (NEN) is a heterogeneous group of tumours and often represents a therapeutic challenge to clinicians. The peptides chromogranin A (CgA), chromogranin B (CgB) and cocaine-and amphetamine-regulated transcript (CART) are widely distributed throughout the neuroendocrine system. CgA and CgB have been used as general NEN biomarkers for many years, while CART has only recently been identified. Of these biomarkers, CgA is the most commonly used. However, circulating CgA concentrations exhibit considerable intra-individual biological variation, are altered by proton pump inhibitors (PPIs) and somatostatin analogues and are elevated in non-NEN malignancies. Therefore, interpretation of CgA results must be in the context of these confounding factors. The effects of treatment and non-NEN conditions on circulating CgB and CART concentrations are less well understood. CgB is less affected by impaired renal function and PPIs than CgA; while, circulating CART concentrations lack a diurnal variation in humans and are more reliable markers of pancreatic NEN malignancy than CgA. The utility of circulating CgA measurements in NEN prognosis, surveillance and disease recurrence has been widely investigated. However, the utility of CgB and CART in NEN management is yet to be elucidated. Further studies are needed to establish whether CgB and CART are useful alternatives to CgA.

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Chromogranin A processing and secretion: specific role of endogenous and exogenous prohormone convertases in the regulated secretory pathway.

Cited by 103 publications

References 55 publications

Neurotrophin-4, Alone or Heterodimerized with Brain-derived Neurotrophic Factor, Is Sorted to the Constitutive Secretory Pathway

Neurotrophin-4, Alone or Heterodimerized with Brain-derived Neurotrophic Factor, Is Sorted to the Constitutive Secretory Pathway

Immunocytochemical Localization of Prohormone Convertases PC1 and PC2 in the Mouse Thyroid Gland and Respiratory Tract

The biochemical utility of chromogranin A, chromogranin B and cocaine- and amphetamine-regulated transcript for neuroendocrine neoplasia

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