PAPP-A: a promising therapeutic target for healthy longevity

Conover, Cheryl A.; Oxvig, Claus

doi:10.1111/acel.12564

Cited by 37 publications

(34 citation statements)

References 78 publications

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“…We found higher levels of peptides for pregnancy‐associated plasma protein A (PAPP‐A) to be associated with increased mortality. Elevations in PAPP‐A levels are present in acute coronary syndromes (Bayes‐Genis et al., ) and have been associated with a number of age‐related disorders, as well as inflammation, prompting a recent suggestion that therapeutic reduction on PAPP‐A may be a strategy to promote healthy aging (Conover & Oxvig, ). The biological underpinnings of other peptides for which levels were positively associated with mortality are less clear but may be worth further investigation.…”

Section: Discussionmentioning

confidence: 99%

High‐throughput serum proteomics for the identification of protein biomarkers of mortality in older men

et al. 2018

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SummaryThe biological perturbations associated with incident mortality are not well elucidated, and there are limited biomarkers for the prediction of mortality. We used a novel high‐throughput proteomics approach to identify serum peptides and proteins associated with 5‐year mortality in community‐dwelling men age ≥65 years who participated in a longitudinal observational study of musculoskeletal aging (Osteoporotic Fractures in Men: MrOS). In a discovery phase, serum specimens collected at baseline in 2473 men were analyzed using liquid chromatography–ion mobility–mass spectrometry, and incident mortality in the subsequent 5 years was ascertained by tri‐annual questionnaire. Rigorous statistical methods were utilized to identify 56 peptides (31 proteins) that were associated with 5‐year mortality. In an independent replication phase, selected reaction monitoring was used to examine 21 of those peptides in baseline serum from 750 additional men; 81% of those peptides remained significantly associated with mortality. Mortality‐associated proteins included a variety involved in inflammation or complement activation; several have been previously linked to mortality (e.g., C‐reactive protein, alpha 1‐antichymotrypsin) and others are not previously known to be associated with mortality. Other novel proteins of interest included pregnancy‐associated plasma protein, VE‐cadherin, leucine‐rich α‐2 glycoprotein 1, vinculin, vitronectin, mast/stem cell growth factor receptor, and Saa4. A panel of peptides improved the predictive value of a commonly used clinical predictor of mortality. Overall, these results suggest that complex inflammatory pathways, and proteins in other pathways, are linked to 5‐year mortality risk. This work may serve to identify novel biomarkers for near‐term mortality.

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Section: Discussionmentioning

confidence: 99%

High‐throughput serum proteomics for the identification of protein biomarkers of mortality in older men

et al. 2018

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“…Future studies will be needed to determine whether Igfbp5 acts by binding to Igf2b to activate Igf1ra and/or Igf1rb in NaR cells. Mammalian cell culture and biochemical studies suggest that IGFBP5 can potentiate IGF action by bringing IGF to the IGF1R through the proteolysis of IGFBP5 or through association with the cellular membrane or extracellular matrix proteins (37,42,43). Whether these mechanisms are involved in Igfbp5a action in NaR cells need to be elucidated with future studies.…”

Section: Discussionmentioning

confidence: 99%

Ca ²⁺ concentration–dependent premature death of igfbp5a ^−/− fish reveals a critical role of IGF signaling in adaptive epithelial growth

Liu

Lewin

et al. 2018

Sci. Signal.

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The phenotype gap is a challenge for genetically dissecting redundant endocrine signaling pathways, such as the six isoforms in the insulin-like growth factor binding protein (IGFBP) family. Although overexpressed IGFBPs can inhibit or potentiate IGF actions or have IGF-independent actions, mutant mice lacking IGFBP-encoding genes do not exhibit major phenotypes. We found that although zebrafish deficient in did not show overt phenotypes when raised in Ca-rich solutions, they died prematurely in low Ca conditions. A group of epithelial cells expressing take up Ca and proliferate under low Ca conditions because of activation of IGF signaling. Deletion of blunted low Ca stress-induced IGF signaling and impaired adaptive proliferation. Reintroducing zebrafish Igfbp5a, but not its ligand binding-deficient mutant, restored adaptive proliferation. Similarly, adaptive proliferation was restored in zebrafish lacking by expression of human IGFBP5, but not two cancer-associated IGFBP5 mutants. Knockdown of IGFBP5 in human colon carcinoma cells resulted in reduced IGF-stimulated cell proliferation. These results reveal a conserved mechanism by which a locally expressed Igfbp regulates organismal Ca homeostasis and survival by activating IGF signaling in epithelial cells and promoting their proliferation in Ca-deficient states. These findings underscore the importance of physiological context when analyzing loss-of-function phenotypes of endocrine factors.

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“…To date, two known proteases have been identified. They include the pregnancy-associated plasma proteins, PAPP-A, and PAPP-A2, which are inhibited by the stanniocalcins (8,9). In addition, the ligands, as well as binding proteins, have been shown to interact with IGF family receptors to exert unique effects that are cell and tissue dependent (10,11).…”

Section: The Igf Systemmentioning

confidence: 99%

The IGF/Insulin-IGFBP Axis in Corneal Development, Wound Healing, and Disease

2020

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The insulin-like growth factor (IGF) family plays key roles in growth and development. In the cornea, IGF family members have been implicated in proliferation, differentiation, and migration, critical events that maintain a smooth refracting surface that is essential for vision. The IGF family is composed of multiple ligands, receptors, and ligand binding proteins. Expression of IGF type 1 receptor (IGF-1R), IGF type 2 receptor (IGF-2R), and insulin receptor (INSR) in the cornea has been well characterized, including the presence of the IGF-1R and INSR hybrid (Hybrid-R) in the corneal epithelium. Recent data also indicates that each of these receptors display unique intracellular localization. Thus, in addition to canonical ligand binding at the plasma membrane and the initiation of downstream signaling cascades, IGF-1R, INSR, and Hybrid-R also function to regulate mitochondrial stability and nuclear gene expression. IGF-1 and IGF-2, two of three principal ligands, are polypeptide growth factors that function in all cellular layers of the cornea. Unlike IGF-1 and IGF-2, the hormone insulin plays a unique role in the cornea, different from many other tissues in the body. In the corneal epithelium, insulin is not required for glucose uptake, due to constitutive activation of the glucose transporter, GLUT1. However, insulin is needed for the regulation of metabolism, circadian rhythm, autophagy, proliferation, and migration after wounding. There is conflicting evidence regarding expression of the six IGF-binding proteins (IGFBPs), which function primarily to sequester IGF ligands. Within the cornea, IGFBP-2 and IGFBP-3 have identified roles in tissue homeostasis. While IGFBP-3 regulates growth control and intracellular receptor localization in the corneal epithelium, both IGFBP-2 and IGFBP-3 function in corneal fibroblast differentiation and myofibroblast proliferation, key events in stromal wound healing. IGFBP-2 has also been linked to cellular overgrowth in pterygium. There is a clear role for IGF family members in regulating tissue homeostasis in the cornea. This review summarizes what is known regarding the function of IGF and related proteins in corneal development, during wound healing, and in the pathophysiology of disease. Finally, we highlight key areas of research that are in need of future study.

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PAPP-A: a promising therapeutic target for healthy longevity

Cited by 37 publications

References 78 publications

High‐throughput serum proteomics for the identification of protein biomarkers of mortality in older men

High‐throughput serum proteomics for the identification of protein biomarkers of mortality in older men

Ca ²⁺ concentration–dependent premature death of igfbp5a ^−/− fish reveals a critical role of IGF signaling in adaptive epithelial growth

The IGF/Insulin-IGFBP Axis in Corneal Development, Wound Healing, and Disease

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PAPP-A: a promising therapeutic target for healthy longevity

Cited by 37 publications

References 78 publications

High‐throughput serum proteomics for the identification of protein biomarkers of mortality in older men

High‐throughput serum proteomics for the identification of protein biomarkers of mortality in older men

Ca 2+ concentration–dependent premature death of igfbp5a −/− fish reveals a critical role of IGF signaling in adaptive epithelial growth

The IGF/Insulin-IGFBP Axis in Corneal Development, Wound Healing, and Disease

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Ca ²⁺ concentration–dependent premature death of igfbp5a ^−/− fish reveals a critical role of IGF signaling in adaptive epithelial growth