Activation and Routing of Membrane-tethered Prohormone Convertases 1 and 2

Bruzzaniti, Angela; Marx, Ruth; Mains, Richard E.

doi:10.1074/jbc.274.35.24703

Cited by 18 publications

(7 citation statements)

References 98 publications

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“…Because POMC is processed to produce several products other than ACTH, the potential for ACTH to be produced widely is apparent. Normally, however, cells that produce other melanocorticins do so with high specificity due to a number of factors including modification of the processing enzymes that channel the products to those specific to individual sites 33 . On the other hand, there are reports of ACTH production by human macrophage/ monocyte cells, 34 so it is possible that some stimulation of ACTH receptors may occur in bone independently of pituitary ACTH.…”

Section: Pituitary Glycoproteins Are Produced Outside Of the Pituitarymentioning

confidence: 99%

Skeletal receptors for steroid‐family regulating glycoprotein hormones

Blair

Robinson

Sun

et al. 2011

Annals of the New York Academy of Sciences

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Pituitary glycoprotein hormone receptors, including ACTH-R, TSH-R, and FSH-R, occur in bone. Their skeletal expression reflects that central endocrine control is evolutionarily recent. ACTH receptors, in osteoblasts or the adrenal cortex, drive VEGF synthesis. VEGF is essential to maintain vasculature. In bone, ACTH suppression by glucocorticoids can cause osteonecrosis. TSH receptors occur on osteoblasts and osteoclasts, in both cases reducing activity. Thus, TSH directly reduces skeletal turnover, consistent with evolutionary adaptation to stress. FSH receptors accelerate bone resorption, whereas estrogen promotes bone formation, the forces usually balancing. With ovarian failure, low estrogen with high FSH causes rapid bone loss. The skeletal FSH effect in the menopause seems paradoxical, but it is a logical adaptation in lactation, where prolonged FSH elevation also occurs. In addition to receptors, there is some synthesis of pituitary glycoproteins at distributed sites; this is not well studied, but it may further modify the paradigm of central endocrine regulation.

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Section: Pituitary Glycoproteins Are Produced Outside Of the Pituitarymentioning

confidence: 99%

Skeletal receptors for steroid‐family regulating glycoprotein hormones

Blair

Robinson

Sun

et al. 2011

Annals of the New York Academy of Sciences

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“…Recombinant adenoviruses have been described previously (15): PAM-1V encodes full length rat PAM-1 (nucleotides 293-3245); POMCV encodes mouse POMC (nucleotides 1-920); Myc-TMD/CDV encodes a chimeric protein described previously (10) in which the PAM signal (amino acids 1-26; nucleotides 298 -375) and the pro-domain (amino acids 27-35; nucleotides 376 -420) were fused in frame to Myc epitope followed by the transmembrane domain (TMD) and cytoplasmic domain (CD) (amino acids 858 -976; nucleotides 2871-3225) of PAM. For recombinant adenovirus constructions, cDNAs were subcloned into the virus shuttle vector (pAdLox) as described previously for PAM-1V and POMCV (15).…”

Section: Methodsmentioning

confidence: 99%

“…In this chimeric protein (Fig. 3A), the PAM signal and NH 2 -terminal regions allow the Myc epitope tag, which precedes the transmembrane and cytoplasmic domains of PAM, to adopt a lumenal location (10).…”

Section: Subcellular Localization Of Virally Encoded Pam In Anterior mentioning

confidence: 99%

“…Membrane proteins lacking the cytosolic domain are less extensively cleaved by secretory granule endoproteases, accumulate on the plasma membrane, and fail to undergo internalization. A marker protein lacking both catalytic domains of PAM, consisting only of the PAM signal sequence followed by its transmembrane/cytosolic domain, is highly localized to the TGN region of AtT-20 cells (10); appending the cytosolic domain of PAM to Tac, a plasma membrane protein, rerouted Tac to the TGN (11). The cytosolic tail of PAM interacts with proteins that affect cytoskeletal organization and expression of membrane PAM alters the organization of the actin cytoskeleton, perhaps explaining the ability of membrane PAM to affect secretory granule biogenesis (12).…”

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confidence: 99%

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Targeting of Membrane Proteins to the Regulated Secretory Pathway in Anterior Pituitary Endocrine Cells

Meskini

Galano

Marx

et al. 2001

Journal of Biological Chemistry

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Unlike the neuroendocrine cell lines widely used to study trafficking of soluble and membrane proteins to secretory granules, the endocrine cells of the anterior pituitary are highly specialized for the production of mature secretory granules. Therefore, we investigated the trafficking of three membrane proteins in primary anterior pituitary endocrine cells. Peptidylglycine ␣-amidating monooxygenase (PAM), an integral membrane protein essential to the production of many bioactive peptides, is cleaved and enters the regulated secretory pathway even when expressed at levels 40-fold higher than endogenous levels. Myc-TMD/CD, a membrane protein lacking the lumenal, catalytic domains of PAM, is still stored in granules. Secretory granules are not the default pathway for all membrane proteins, because Tac accumulates on the surface of pituitary endocrine cells. Overexpression of PAM is accompanied by a diminution in its endoproteolytic cleavage and in its BaCl 2 -stimulated release from mature granules. Because internalized PAM/PAM-antibody complexes are returned to secretory granules, the endocytic machinery of the pituitary endocrine cells is not saturated. As in corticotrope tumor cells, expression of PAM or Myc-TMD/CD alters the organization of the actin cytoskeleton. PAM-mediated alterations in the cytoskeleton may limit maturation of PAM and storage in mature granules.Peptidylglycine ␣-amidating monooxygenase (PAM) 1 is a bifunctional enzyme involved in the posttranslational processing of many prohormones and neuropeptides. PAM catalyzes the formation of ␣-amidated peptides from peptide precursor molecules with a COOH-terminal glycine. In neurons and endocrine cells, biologically active peptides are stored in secretory granules that undergo regulated release in response to external stimuli. Localized in secretory granules of many neural and endocrine tissues, PAM is one of a small number of posttranslational processing enzyme occurring naturally in soluble and membrane forms (1-4). For this reason, we have used PAM to investigate the trafficking of soluble and membrane proteins into secretory granules (5, 6).Soluble and membrane PAM are targeted to the regulated secretory pathway in different ways (5, 6). By stably expressing wild type and mutant PAM in AtT-20 corticotrope tumor cells, protein domains containing trafficking information were identified (7-9). The two catalytic domains of PAM can be expressed independently, and both are efficiently targeted to secretory granules. In contrast, membrane PAM is predominantly localized in the trans-Golgi network (TGN) at steady state. The small amount of membrane PAM on the cell surface is rapidly internalized and accumulates in the TGN region (7). The cytosolic domain of PAM contains information necessary for the trafficking of this membrane protein within the secretory pathway (7). Membrane proteins lacking the cytosolic domain are less extensively cleaved by secretory granule endoproteases, accumulate on the plasma membrane, and fail to undergo internalization. A m...

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“…Medium samples from the second basal and stimulation collections, and cell extracts were assayed for PHM activity (Kolhekar et al, 1997) using 125 Ilabeled ␣-N-acetyl-Tyr-Val-Gly as substrate. Samples were assayed in duplicate, and reactions were carried out for 2 h. ACTH secretion and cell content were measured by radioimmunoassay using antibody Kathy, directed against the C-terminal of ACTH (Bruzzaniti et al, 1999). For quantification of PHMmGFP secretion from GH3 cells, media, and cell lysates were fractionated by SDS-PAGE, transferred to PVDF, and probed with GFP Ab (Abcam); signals in the linear range were quantified using GeneTools software (Syngene, Frederick, MD).…”

Section: Secretion Experiments Enzyme Assays and Radioimmunoassaysmentioning

confidence: 99%

Not All Secretory Granules Are Created Equal: Partitioning of Soluble Content Proteins

Sobota

Ferraro

Back

et al. 2006

MBoC

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Secretory granules carrying fluorescent cargo proteins are widely used to study granule biogenesis, maturation, and regulated exocytosis. We fused the soluble secretory protein peptidylglycine ␣-hydroxylating monooxygenase (PHM) to green fluorescent protein (GFP) to study granule formation. When expressed in AtT-20 or GH3 cells, the PHM-GFP fusion protein partitioned from endogenous hormone (adrenocorticotropic hormone, growth hormone) into separate secretory granule pools. Both exogenous and endogenous granule proteins were stored and released in response to secretagogue. Importantly, we found that segregation of content proteins is not an artifact of overexpression nor peculiar to GFP-tagged proteins. Neither luminal acidification nor cholesterol-rich membrane microdomains play essential roles in soluble content protein segregation. Our data suggest that intrinsic biophysical properties of cargo proteins govern their differential sorting, with segregation occurring during the process of granule maturation. Proteins that can self-aggregate are likely to partition into separate granules, which can accommodate only a few thousand copies of any content protein; proteins that lack tertiary structure are more likely to distribute homogeneously into secretory granules. Therefore, a simple "self-aggregation default" theory may explain the little acknowledged, but commonly observed, tendency for both naturally occurring and exogenous content proteins to segregate from each other into distinct secretory granules. INTRODUCTIONThe cellular life of secretory proteins begins with the cotranslational translocation of their nascent polypeptide chains into the lumen of the endoplasmic reticulum (ER). These proteins then proceed in the anterograde direction, through the Golgi complex and into the trans-Golgi network (TGN), which is considered a "sorting station" for secretory proteins (Farquhar and Palade, 1981). At the TGN, vesicles destined for different subcellular compartments bud while acquiring their cargo. In all cell types, a "constitutive secretory pathway" delivers soluble and membrane secretory proteins necessary for housekeeping functions to the appropriate compartment (e.g., plasma membrane or endosomes/ lysosomes; Turner and Arvan, 2000). Besides this constitutive pathway, specialized cell types such as endocrine, exocrine, neuroendocrine cells, and neurons possess a "regulated pathway" in which specialized organelles, the secretory granules, store proteins for release in response to an incoming signal (Arvan and Castle, 1998). The soluble proteins found in constitutive vesicles and regulated secretory granules differ, and the processes responsible for this segregation are the object of intensive investigation.Two models, "sorting for entry" and "sorting by retention," both having experimental support, have been proposed to explain how sorting of soluble content proteins occurs (Arvan and Castle, 1998). The sorting for entry hypothesis postulates the existence of one or more "membrane receptors" able to selectivel...

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Activation and Routing of Membrane-tethered Prohormone Convertases 1 and 2

Cited by 18 publications

References 98 publications

Skeletal receptors for steroid‐family regulating glycoprotein hormones

Skeletal receptors for steroid‐family regulating glycoprotein hormones

Targeting of Membrane Proteins to the Regulated Secretory Pathway in Anterior Pituitary Endocrine Cells

Not All Secretory Granules Are Created Equal: Partitioning of Soluble Content Proteins

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