ADAMs, a disintegrin and metalloproteinases, mediate shedding of oxytocinase

Ito, Norio; Nomura, Seiji; Iwase, Akira; Ito, Tomomi; Kikkawa, Fumitaka; Tsujimoto, Masafumi; Ishiura, Shoichi; Mizutani, Shigehiko

doi:10.1016/j.bbrc.2003.12.183

Cited by 83 publications

(49 citation statements)

References 28 publications

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“…IRAP/P-LAP is well expressed in human placenta and is released into the circulation after cleavage of its extracellular domain from the transmembrane domain (14). Our results do not support a crucial role for IRAP/P-LAP in the cleavage of oxytocin in nonpregnant mice.…”

Section: Discussioncontrasting

confidence: 49%

Vasopressin is a physiological substrate for the insulin-regulated aminopeptidase IRAP

Wallis

Lankford²,

Keller³

2007

American Journal of Physiology-Endocrinology and Metabolism

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Wallis MG, Lankford MF, Keller SR. Vasopressin is a physiological substrate for the insulin-regulated aminopeptidase IRAP. Am J Physiol Endocrinol Metab 293: E1092-E1102, 2007. First published August 7, 2007; doi:10.1152/ajpendo.00440.2007.-Insulin-regulated aminopeptidase (IRAP) is a membrane aminopeptidase and is homologous to the placental leucine aminopeptidase, P-LAP. IRAP has a wide distribution but has been best characterized in adipocytes and myocytes. In these cells, IRAP colocalizes with the glucose transporter GLUT4 to intracellular vesicles and, like GLUT4, translocates from these vesicles to the cell surface in response to insulin. Earlier studies demonstrated that purified IRAP cleaves several peptide hormones and that, concomitant with the appearance of IRAP at the surface of insulin-stimulated adipocytes, aminopeptidase activity toward extracellular substrates increases. In the present study, to identify in vivo substrates for IRAP, we tested potential substrates for cleavage by IRAP-deficient (IRAP Ϫ/Ϫ ) and control mice. We found that vasopressin and oxytocin were not processed from the NH2 terminus by isolated IRAP Ϫ/Ϫ adipocytes and skeletal muscles. Vasopressin was not cleaved from the NH2 terminus after injection into IRAP Ϫ/Ϫ mice and exhibited a threefold increased half-life in the circulation of IRAP Ϫ/Ϫ mice. Consistent with this finding, endogenous plasma vasopressin levels were elevated twofold in IRAP Ϫ/Ϫ mice, and vasopressin levels in IRAP Ϫ/Ϫ brains, where plasma vasopressin originates, showed a compensatory decrease. We further established that insulin increased the clearance of vasopressin from control but not from IRAP Ϫ/Ϫ mice. In conclusion, we have identified vasopressin as the first physiological substrate for IRAP. Changes in plasma and brain vasopressin levels in IRAP Ϫ/Ϫ mice suggest a significant role for IRAP in regulating vasopressin. We have also uncovered a novel IRAP-dependent insulin effect: to acutely modify vasopressin.peptide hormone cleavage; insulin-regulated aminopeptidase-deficient mice; insulin action THE INSULIN-REGULATED AMINOPEPTIDASE (IRAP) is a member of the family of zinc-dependent membrane aminopeptidases and is the homologue of the human placental leucine aminopeptidase (P-LAP) (16). IRAP has a wide tissue distribution (18, 34) but in each of the tissues is expressed only in specific cell types (28). In all cells so far examined, IRAP is found in an intracellular location and is recruited to the cell surface in response to different stimuli (reviewed in Ref. 16). The subcellular localization of IRAP and regulation thereof have been best characterized in adipocytes and muscle cells (reviewed in Ref. 16). In these cells, under basal conditions, IRAP is sequestered within intracellular vesicles that also harbor the insulin-responsive glucose transporter GLUT4. In response to insulin, IRAP, like GLUT4, translocates from the intracellular vesicles to the cell surface. In adipocytes, this results in a 6-to 8-and 10-to 20-fold increase of IRAP and GLUT4, ...

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Section: Discussioncontrasting

confidence: 49%

Vasopressin is a physiological substrate for the insulin-regulated aminopeptidase IRAP

Wallis

Lankford²,

Keller³

2007

American Journal of Physiology-Endocrinology and Metabolism

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“…These proteinases are highly expressed in human placenta and are present at high concentrations in maternal serum as early as the first trimester (29). ADAM12 serum concentrations are known to be significantly reduced in pregnancies complicated by fetal trisomy 18 and trisomy 21 and may therefore be of potential use in conjunction with cell-free DNA for the detection of chromosomal abnormalities (30,31). Similarly, placental alkaline phosphatase, encoded by the ALPP gene, is a tissue-specific isoform expressed increasingly throughout pregnancy until term in the placenta (32,33).…”

Section: −9mentioning

confidence: 99%

Noninvasive in vivo monitoring of tissue-specific global gene expression in humans

Koh¹,

Pan²,

Gawad³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

276

256

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Significance Circulating cell-free RNA in the blood provides a potential window into the health, phenotype, and developmental programs of a variety of human organs. We used high-throughput methods of RNA analysis such as microarrays and next-generation sequencing to characterize the global landscape of circulating RNA in human subjects. By focusing on tissue-specific genes, we were able to identify the relative contributions of these tissues to circulating RNA and monitor changes during tissue development and neurodegenerative disease states.

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“…Discrepancies exist related to ADAM12 expression within the placenta, where previous studies have localized ADAM12 to the apical membrane 20,22,39 and cytoplasm 22 of the synCT, as well as stochastically within vCTs. 22 Further, we 20 and others 21 have localized ADAM12 to EVTs; together these data show that ADAM12 is expressed by multiple trophoblast subtypes and imply that ADAM12 has diverse functions in placentation.…”

Section: Discussionmentioning

confidence: 99%

ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion

et al. 2015

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Trophoblasts, placental cells of epithelial lineage, undergo extensive differentiation to form the cellular components of the placenta. Trophoblast progenitor cell differentiation into the multinucleated syncytiotrophoblast is a key developmental process required for placental function, where defects in syncytiotrophoblast formation and turnover associate with placental pathologies and link to poor pregnancy outcomes. The cellular and molecular processes governing syncytiotrophoblast formation are poorly understood, but require the activation of pathways that direct cell fusion. The protease, A Disintegrin and Metalloproteinase 12 (ADAM12), controls cell fusion in myoblasts and is highly expressed in the placenta localizing to multiple trophoblast populations. However, the importance of ADAM12 in regulating trophoblast fusion is unknown. Here, we describe a function for ADAM12 in regulating trophoblast fusion. Using two distinct trophoblast models of cell fusion, we show that ADAM12 is dynamically upregulated and is under the transcriptional control of protein kinase A. siRNA-directed loss of ADAM12 impedes spontaneous fusion of primary cytotrophoblasts, whereas overexpression of the secreted variant, ADAM12S, potentiates cell fusion in the Bewo trophoblast cell line. Mechanistically, both ectopic and endogenous levels of ADAM12 were shown to control trophoblast fusion through E-cadherin ectodomain shedding and remodeling of intercellular boundaries. This study describes a novel role for ADAM12 in placental development, specifically highlighting its importance in controlling the differentiation of villous cytotrophoblasts into multinucleated cellular structures. Moreover, this work identifies E-cadherin as a novel ADAM12 substrate, and highlights the significance that cell adhesion molecule ectodomain shedding has in normal development. Cell Death and Differentiation (2015) 22, 1970-1984 doi:10.1038/cdd.2015 published online 24 April 2015 In mammalian development, the placenta forms the mechanical and physiological link between maternal and fetal circulations. In rodents and higher order primates, including humans, this transfer is achieved through extensive uterine infiltration by fetal-derived cells of epithelial lineage called trophoblasts.1 Trophoblast differentiation is essential for optimal placental function, where the underlying molecular processes regulating specific functions of distinct trophoblast populations are strictly controlled. Defects in trophoblast differentiation associate with impaired placental function and directly impact fetal and maternal health. Within the placenta, progenitor trophoblasts (also called villous cytotrophoblasts; vCTs) overlie a well-defined basal lamina forming an organized, mitotically active epithelial layer. vCT differentiation into an overlying multinucleated structure called the syncytiotrophoblast (synCT) is a key event in placental development. 3 The synCT, composed of millions of nuclei sharing one common cytoplasm, directs nutrient and gas exchange between m...

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ADAMs, a disintegrin and metalloproteinases, mediate shedding of oxytocinase

Cited by 83 publications

References 28 publications

Vasopressin is a physiological substrate for the insulin-regulated aminopeptidase IRAP

Vasopressin is a physiological substrate for the insulin-regulated aminopeptidase IRAP

Noninvasive in vivo monitoring of tissue-specific global gene expression in humans

ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion

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