Gene Symbol: Pappa
Description: pregnancy-associated plasma protein A
Alias: 8430414N03Rik, IGFBP-4ase, PAG1, PAPP-A, pappalysin-1, IGF-dependent IGFBP-4 protease, insulin-like growth factor-dependent IGF-binding protein 4 protease
Species: mouse
Products:     Pappa

Top Publications

  1. Søe R, Overgaard M, Thomsen A, Laursen L, Olsen I, Sottrup Jensen L, et al. Expression of recombinant murine pregnancy-associated plasma protein-A (PAPP-A) and a novel variant (PAPP-Ai) with differential proteolytic activity. Eur J Biochem. 2002;269:2247-56 pubmed
    ..Importantly, these data support the development of the mouse as a model organism for the study of PAPP-A, which must take into account the differences between the mouse and the human. ..
  2. Qin X, Sexton C, Byun D, Strong D, Baylink D, Mohan S. Differential regulation of pregnancy associated plasma protein (PAPP)-A during pregnancy in human and mouse. Growth Horm IGF Res. 2002;12:359-66 pubmed
    ..2) The lack of an increase in serum IGFBP-4 proteolytic activity during mouse pregnancy is due to the low level of PAPP-A expression in the placenta. ..
  3. Conover C, Bale L, Overgaard M, Johnstone E, Laursen U, Füchtbauer E, et al. Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development. Development. 2004;131:1187-94 pubmed
    Pregnancy-associated plasma protein A (PAPPA) is a metzincin superfamily metalloproteinase in the insulin-like growth factor (IGF) system...
  4. Vallejo A, Michel J, Bale L, Lemster B, Borghesi L, Conover C. Resistance to age-dependent thymic atrophy in long-lived mice that are deficient in pregnancy-associated plasma protein A. Proc Natl Acad Sci U S A. 2009;106:11252-7 pubmed publisher
    Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase that controls the tissue availability of insulin-like growth factor (IGF). Homozygous deletion of PAPPA in mice leads to lifespan extension...
  5. Conover C, Bale L, Mader J, Mason M, Keenan K, Marler R. Longevity and age-related pathology of mice deficient in pregnancy-associated plasma protein-A. J Gerontol A Biol Sci Med Sci. 2010;65:590-9 pubmed publisher
    ..In summary, the major contributors to the extended life span of PAPP-A KO mice are delayed occurrence of fatal neoplasias and decreased incidence of age-related degenerative changes. ..
  6. Van Leuven F, Torrekens S, Van den Berghe H. Isolation, characterization and partial sequencing of Pregnancy Associated Mouse Protein PAMP1 identifies it as a novel female specific protein, unrelated to the alpha-2-macroglobulin family of proteinase inhibitors. FEBS Lett. 1993;322:219-22 pubmed
    ..The physicochemical and the sequence data thus establish this protein as a novel, female-specific protein, but unrelated to the Macroglobulin proteinase inhibitor family. ..
  7. Poltorak A, He X, Smirnova I, Liu M, Van Huffel C, Du X, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282:2085-8 pubmed
    ..Destructive mutations of Tlr4 predispose to the development of Gram-negative sepsis, leaving most aspects of immune function intact. ..
  8. Conover C, Mason M, Levine J, Novak C. Metabolic consequences of pregnancy-associated plasma protein-A deficiency in mice: exploring possible relationship to the longevity phenotype. J Endocrinol. 2008;198:599-605 pubmed publisher
    ..These findings are discussed in the context of those from other long-lived mouse models. ..
  9. Bale L, Chakraborty S, Conover C. Inducible reduction in pregnancy-associated plasma protein-A gene expression inhibits established atherosclerotic plaque progression in mice. Endocrinology. 2014;155:1184-7 pubmed publisher
    ..These data indicate PAPP-A as a potential target to limit progression of established atherosclerotic plaque. ..

More Information


  1. Swindell W. Accelerated failure time models provide a useful statistical framework for aging research. Exp Gerontol. 2009;44:190-200 pubmed publisher
    ..In addition, from the standpoint of aging research, these statistical approaches have appealing properties and provide valuable tools for the analysis of survivorship data. ..
  2. Nyegaard M, Overgaard M, Su Y, Hamilton A, Kwintkiewicz J, Hsieh M, et al. Lack of functional pregnancy-associated plasma protein-A (PAPPA) compromises mouse ovarian steroidogenesis and female fertility. Biol Reprod. 2010;82:1129-38 pubmed publisher
    ..Pregnancy-associated plasma protein-A (PAPPA) is a secreted metalloprotease responsible for cleavage of IGFBP4 in the ovary...
  3. Mikkelsen J, Gyrup C, Kristensen P, Overgaard M, Poulsen C, Laursen L, et al. Inhibition of the proteolytic activity of pregnancy-associated plasma protein-A by targeting substrate exosite binding. J Biol Chem. 2008;283:16772-80 pubmed publisher
  4. Bale L, West S, Conover C. Inducible knockdown of pregnancy-associated plasma protein-A gene expression in adult female mice extends life span. Aging Cell. 2017;16:895-897 pubmed publisher
    ..004 for >1000 days). Thus, survival curves and age-specific mortality indicate that female mice with knockdown of PAPP-A gene expression as adults have an extended healthy life span. ..
  5. Conover C, Bale L, Powell D. Inducible knock out of pregnancy-associated plasma protein-a gene expression in the adult mouse: effect on vascular injury response. Endocrinology. 2013;154:2734-8 pubmed publisher
    ..0001) reduction of neointimal formation in these mice after unilateral carotid artery ligation. ..
  6. Mader J, Resch Z, McLean G, Mikkelsen J, Oxvig C, Marler R, et al. Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy. J Endocrinol. 2013;219:51-8 pubmed publisher
    ..These data suggest PAPP-A as a potential therapeutic target for diabetic nephropathy. ..
  7. Conover C, Harstad S, Tchkonia T, Kirkland J. Preferential impact of pregnancy-associated plasma protein-A deficiency on visceral fat in mice on high-fat diet. Am J Physiol Endocrinol Metab. 2013;305:E1145-53 pubmed publisher
    ..Thus, PAPP-A may be a potential target for treatment and/or prevention strategies for visceral obesity and related morbidities. ..
  8. Steffensen L, Conover C, Bjørklund M, Ledet T, Bentzon J, Oxvig C. Stanniocalcin-2 overexpression reduces atherosclerosis in hypercholesterolemic mice. Atherosclerosis. 2016;248:36-43 pubmed publisher
    ..Furthermore, we demonstrate that lesion development can be inhibited in an experimental model by driving the balance towards inhibited PAPP-A. ..
  9. Conover C, Bale L, Nair K. Comparative gene expression and phenotype analyses of skeletal muscle from aged wild-type and PAPP-A-deficient mice. Exp Gerontol. 2016;80:36-42 pubmed publisher
    ..Moreover, 18-month-old PAPP-A KO mice exhibited significantly enhanced endurance running on a treadmill. Thus, PAPP-A deficiency in mice is associated with indices of healthy skeletal muscle function with age. ..
  10. Qureshi S, Lariviere L, Leveque G, Clermont S, Moore K, Gros P, et al. Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J Exp Med. 1999;189:615-25 pubmed
    ..Identification of distinct mutations involving the same gene at the Lps locus in two different hyporesponsive inbred mouse strains strongly supports the hypothesis that altered Tlr4 function is responsible for endotoxin tolerance. ..
  11. Tanner S, Hefferan T, Rosen C, Conover C. Impact of pregnancy-associated plasma protein-a deletion on the adult murine skeleton. J Bone Miner Res. 2008;23:655-62 pubmed
    ..The data suggest a primary role for PAPP-A in modulating local IGF bioavailability for trabecular bone remodeling. ..
  12. Hourvitz A, Kuwahara A, Hennebold J, Tavares A, Negishi H, Lee T, et al. The regulated expression of the pregnancy-associated plasma protein-A in the rodent ovary: a proposed role in the development of dominant follicles and of corpora lutea. Endocrinology. 2002;143:1833-44 pubmed
    ..Accordingly, successful antral follicle development, ovulation, and corpus luteum formation may be contingent on an IGFBP-4-deplete/PAPP-A-replete circumstance, hence resulting in an IGF-I-replete intrafollicular microenvironment. ..
  13. Qin X, Wergedal J, Rehage M, Tran K, Newton J, Lam P, et al. Pregnancy-associated plasma protein-A increases osteoblast proliferation in vitro and bone formation in vivo. Endocrinology. 2006;147:5653-61 pubmed
    ..Thus, enhancing IGF bioavailability by PAPP-A can be a powerful strategy in the treatment of certain metabolic diseases such as osteoporosis. ..
  14. Clifton K, Conover C. Pregnancy-associated plasma protein-A modulates the anabolic effects of parathyroid hormone in mouse bone. Bone. 2015;81:413-6 pubmed publisher
    ..These data suggest that stimulation of PAPP-A expression by intermittent PTH treatment contributes to PTH bone anabolism in mice. ..
  15. Nakasato M, Kohsaka H, Mizutani T, Watanabe G, Taya K, Nagaoka K. Pregnancy-associated plasma protein (PAPP)-A expressed in the mammary gland controls epithelial cell proliferation and differentiation. Endocrine. 2013;43:387-93 pubmed publisher
    ..In contrast, during mid-late pregnancy, local PAPP-A expression begins and enhances cell differentiation within mammary epithelial cell. ..
  16. Chander H, Halpern M, Resnick Silverman L, Manfredi J, Germain D. Skp2B overexpression alters a prohibitin-p53 axis and the transcription of PAPP-A, the protease of insulin-like growth factor binding protein 4. PLoS ONE. 2011;6:e22456 pubmed publisher
    ..Therefore, these findings indicate that the defect in p53 function and the increased proteolysis of IGFBP-4, we had observed, represent two components of the same pathway, which contributes to the oncogenic function of Skp2B. ..
  17. Yang T, Thoreson A, An K, Zhao C, Conover C, Amadio P. PAPP-A affects tendon structure and mechanical properties. J Struct Biol. 2015;192:59-66 pubmed publisher
    ..05) and smaller hysteresis area (p<0.05) than KO mice, and larger normalized tendon CSA (p<0.05) than WT mice. Based on these data, we conclude that PAPP-A affects fascicle structure, thereby affecting tendon phenotype. ..
  18. Conover C, Bale L, Oxvig C. Targeted Inhibition of Pregnancy-Associated Plasma Protein-A Activity Reduces Atherosclerotic Plaque Burden in Mice. J Cardiovasc Transl Res. 2016;9:77-9 pubmed publisher
    ..This study demonstrates proof-of-principle and provides feasibility for a novel therapeutic strategy to inhibit atherosclerotic plaque burden by selective targeting of PAPP-A. ..
  19. Phang D, Rehage M, Bonafede B, Hou D, Xing W, Mohan S, et al. Inactivation of insulin-like-growth factors diminished the anabolic effects of pregnancy-associated plasma protein-A (PAPP-A) on bone in mice. Growth Horm IGF Res. 2010;20:192-200 pubmed publisher
    ..bioavailability and that other alternative pathways may play a negligible role in mediating the anabolic effect of PAPPA in bone...
  20. Miller B, Bronk J, Nishiyama T, Yamagiwa H, Srivastava A, Bolander M, et al. Pregnancy associated plasma protein-A is necessary for expeditious fracture healing in mice. J Endocrinol. 2007;192:505-13 pubmed
    ..The ability of PAPP-A to enhance local IGF action may be an important mechanism for optimizing the fracture repair response. ..
  21. Zagoraiou L, Akay T, Martin J, Brownstone R, Jessell T, Miles G. A cluster of cholinergic premotor interneurons modulates mouse locomotor activity. Neuron. 2009;64:645-62 pubmed publisher
    ..Thus, V0(C) interneurons represent a defined class of spinal cholinergic interneurons with an intrinsic neuromodulatory role in the control of locomotor behavior. ..
  22. Tomlinson E, Fu L, John L, Hultgren B, Huang X, Renz M, et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology. 2002;143:1741-7 pubmed
    ..Consistent with the reduction in expression of acetyl CoA carboxylase 2, liver triglyceride levels were reduced. ..
  23. Dominick G, Bowman J, Li X, Miller R, Garcia G. mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice. Aging Cell. 2017;16:52-60 pubmed publisher
    ..receptor gene disrupted mice (GHRKO), and in this article, mice deficient in the pregnancy-associated protein-A (PAPPA-KO). The ways in which lower mTOR signals slow aging and age-related diseases are, however, not well characterized...
  24. Harstad S, Conover C. Tissue-specific changes in pregnancy associated plasma protein-A expression with age in mice. Exp Gerontol. 2014;57:13-7 pubmed publisher
    ..Thus, tissue-specific PAPP-A expression in mice is differentially affected during aging, and may regulate local IGF-I bioactivity in certain tissues. ..
  25. Ning Y, Schuller A, Conover C, Pintar J. Insulin-like growth factor (IGF) binding protein-4 is both a positive and negative regulator of IGF activity in vivo. Mol Endocrinol. 2008;22:1213-25 pubmed publisher
  26. Spies T, DeMars R. Restored expression of major histocompatibility class I molecules by gene transfer of a putative peptide transporter. Nature. 1991;351:323-4 pubmed
    ..No similar effect was observed in 721.174 mutant cells, in which a homozygous deletion includes PSF among several other closely linked genes. At least one of these genes may therefore also be required for PSF function. ..
  27. Bale L, Conover C. Disruption of insulin-like growth factor-II imprinting during embryonic development rescues the dwarf phenotype of mice null for pregnancy-associated plasma protein-A. J Endocrinol. 2005;186:325-31 pubmed
    ..These data provide strong genetic evidence that PAPP-A plays an essential role in determining IGF-II bioavailability for optimal fetal growth and development. ..
  28. Wagner P, Christians J. Altered placental expression of PAPPA2 does not affect birth weight in mice. Reprod Biol Endocrinol. 2010;8:90 pubmed publisher
    ..RT-PCR to measure the mRNA levels of PAPPA2, as well as mRNA levels of IGFBP-5 (PAPPA2's substrate), and PAPPA (a closely related IGFBP protease) to examine potential feedback and compensation effects...
  29. Glerup S, Kløverpris S, Laursen L, Dagnaes Hansen F, Thiel S, Conover C, et al. Cell surface detachment of pregnancy-associated plasma protein-A requires the formation of intermolecular proteinase-inhibitor disulfide bonds and glycosaminoglycan covalently bound to the inhibitor. J Biol Chem. 2007;282:1769-78 pubmed
    ..Because both PAPP-A and proMBP are expressed ubiquitously, this model may be applicable to many tissues in which insulin-like growth factor bioavailability is locally regulated. ..
  30. Swindell W, Masternak M, Bartke A. In vivo analysis of gene expression in long-lived mice lacking the pregnancy-associated plasma protein A (PappA) gene. Exp Gerontol. 2010;45:366-74 pubmed publisher
    Mice lacking the pregnancy-associated plasma protein A (PappA) gene exhibit diminished localized IGF-1 bioavailability and a 30% increase in mean life span...
  31. Harrington S, Simari R, Conover C. Genetic deletion of pregnancy-associated plasma protein-A is associated with resistance to atherosclerotic lesion development in apolipoprotein E-deficient mice challenged with a high-fat diet. Circ Res. 2007;100:1696-702 pubmed
    ..These data indicate that PAPP-A plays a critical role in lesion development in a mouse model of atherosclerosis, at least in part, through amplification of local IGF-I bioavailability. ..
  32. Resch Z, Simari R, Conover C. Targeted disruption of the pregnancy-associated plasma protein-A gene is associated with diminished smooth muscle cell response to insulin-like growth factor-I and resistance to neointimal hyperplasia after vascular injury. Endocrinology. 2006;147:5634-40 pubmed
    ..Thus, PAPP-A-deficient mice are resistant to neointimal formation after injury, which may be explained in part by the ability of PAPP-A to enhance local IGF-I stimulation of vascular SMCs through proteolysis of IGFBP-4. ..
  33. Austin K, Imam N, Pintar J, Brubaker P. IGF binding protein-4 is required for the growth effects of glucagon-like peptide-2 in murine intestine. Endocrinology. 2015;156:429-36 pubmed publisher
    ..05). Collectively, these results indicate that the IGF-I-modulating protein, IGFBP-4, exerts a negative effect on basal intestinal growth but plays a positive regulatory role in the intestinotropic actions of GLP-2. ..
  34. Boldt H, Bale L, Resch Z, Oxvig C, Overgaard M, Conover C. Effects of mutated pregnancy-associated plasma protein-a on atherosclerotic lesion development in mice. Endocrinology. 2013;154:246-52 pubmed publisher
    ..Thus, PAPP-A exerts its effect while bound to the cell surface in vivo. ..
  35. Conover C, Boldt H, Bale L, Clifton K, Grell J, Mader J, et al. Pregnancy-associated plasma protein-A2 (PAPP-A2): tissue expression and biological consequences of gene knockout in mice. Endocrinology. 2011;152:2837-44 pubmed publisher
    ..In conclusion, tissue expression patterns and biological consequences of gene KO indicate distinct physiological roles for PAPP-A2 and PAPP-A in mice. ..
  36. Rehage M, Mohan S, Wergedal J, Bonafede B, Tran K, Hou D, et al. Transgenic overexpression of pregnancy-associated plasma protein-A increases the somatic growth and skeletal muscle mass in mice. Endocrinology. 2007;148:6176-85 pubmed
    ..Moreover, our studies provide the first experimental evidence that IGFBP degradation is a key determinant in modulating the local action of IGFs in muscle. ..