The Proteinase PAPP-A has Deep Evolutionary Roots Outside of the IGF System

Caroline M.N. Kjeldsen; Claus Oxvig

doi:10.1093/gbe/evaf042

The Proteinase PAPP-A has Deep Evolutionary Roots Outside of the IGF System

Caroline M.N. Kjeldsen
, Claus Oxvig^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

The animal pappalysin metalloproteinases, PAPP-A and PAPP-A2, are highly specific regulatory enzymes of the insulin-like growth factor (IGF) system. Cleavage of their only known substrates, a subset of IGF binding proteins (IGFBPs), releases bioactive IGFI and IGFII, thus promoting IGF signaling. Stanniocalcin-1 and -2 (STC1 and STC2) are potent pappalysin inhibitors, completing the STC-PAPP-A-IGFBP-IGF axis. Utilizing homology searches and phylogenetic analyses, we examined the occurrence of pappalysins in the animal kingdom and their functional conservation. This revealed the extensive presence of pappalysins across metazoans, as well as the presence of 3 pappalysins: PAPP-A, PAPP-A2, and a third group of invertebrate pappalysins, which we name invertebrate PAPP-A (invPAPP-A). We show that PAPP-A and PAPP-A2 arose by duplication during early vertebrate evolution. Despite significant evolutionary distance, the domain architecture of the metazoan pappalysins is completely conserved, and several functional domains and motifs are highly conserved across all pappalysins. However, invPAPP-A exists outside the context of IGFBPs, suggesting that the animal pappalysins may have substrates beyond the IGFBPs for PAPP-A and PAPP-A2 that remain to be discovered. Since PAPP-A is an emerging drug target, it is important to understand potential involvement in regulatory systems other than the IGF system, which might be affected upon targeting of PAPP-A.

Original language	English
Article number	evaf042
Journal	Genome Biology and Evolution
Volume	17
Issue	3
ISSN	1759-6653
DOIs	https://doi.org/10.1093/gbe/evaf042
Publication status	Published - 1 Mar 2025

Keywords

IGF
IGFBP
PAPP-A
PAPP-A2
pappalysin phylogeny
proteinase

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title = "The Proteinase PAPP-A has Deep Evolutionary Roots Outside of the IGF System",

abstract = "The animal pappalysin metalloproteinases, PAPP-A and PAPP-A2, are highly specific regulatory enzymes of the insulin-like growth factor (IGF) system. Cleavage of their only known substrates, a subset of IGF binding proteins (IGFBPs), releases bioactive IGFI and IGFII, thus promoting IGF signaling. Stanniocalcin-1 and -2 (STC1 and STC2) are potent pappalysin inhibitors, completing the STC-PAPP-A-IGFBP-IGF axis. Utilizing homology searches and phylogenetic analyses, we examined the occurrence of pappalysins in the animal kingdom and their functional conservation. This revealed the extensive presence of pappalysins across metazoans, as well as the presence of 3 pappalysins: PAPP-A, PAPP-A2, and a third group of invertebrate pappalysins, which we name invertebrate PAPP-A (invPAPP-A). We show that PAPP-A and PAPP-A2 arose by duplication during early vertebrate evolution. Despite significant evolutionary distance, the domain architecture of the metazoan pappalysins is completely conserved, and several functional domains and motifs are highly conserved across all pappalysins. However, invPAPP-A exists outside the context of IGFBPs, suggesting that the animal pappalysins may have substrates beyond the IGFBPs for PAPP-A and PAPP-A2 that remain to be discovered. Since PAPP-A is an emerging drug target, it is important to understand potential involvement in regulatory systems other than the IGF system, which might be affected upon targeting of PAPP-A.",

keywords = "IGF, IGFBP, PAPP-A, PAPP-A2, pappalysin phylogeny, proteinase",

author = "Kjeldsen, \{Caroline M.N.\} and Claus Oxvig",

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T1 - The Proteinase PAPP-A has Deep Evolutionary Roots Outside of the IGF System

AU - Kjeldsen, Caroline M.N.

AU - Oxvig, Claus

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N2 - The animal pappalysin metalloproteinases, PAPP-A and PAPP-A2, are highly specific regulatory enzymes of the insulin-like growth factor (IGF) system. Cleavage of their only known substrates, a subset of IGF binding proteins (IGFBPs), releases bioactive IGFI and IGFII, thus promoting IGF signaling. Stanniocalcin-1 and -2 (STC1 and STC2) are potent pappalysin inhibitors, completing the STC-PAPP-A-IGFBP-IGF axis. Utilizing homology searches and phylogenetic analyses, we examined the occurrence of pappalysins in the animal kingdom and their functional conservation. This revealed the extensive presence of pappalysins across metazoans, as well as the presence of 3 pappalysins: PAPP-A, PAPP-A2, and a third group of invertebrate pappalysins, which we name invertebrate PAPP-A (invPAPP-A). We show that PAPP-A and PAPP-A2 arose by duplication during early vertebrate evolution. Despite significant evolutionary distance, the domain architecture of the metazoan pappalysins is completely conserved, and several functional domains and motifs are highly conserved across all pappalysins. However, invPAPP-A exists outside the context of IGFBPs, suggesting that the animal pappalysins may have substrates beyond the IGFBPs for PAPP-A and PAPP-A2 that remain to be discovered. Since PAPP-A is an emerging drug target, it is important to understand potential involvement in regulatory systems other than the IGF system, which might be affected upon targeting of PAPP-A.

AB - The animal pappalysin metalloproteinases, PAPP-A and PAPP-A2, are highly specific regulatory enzymes of the insulin-like growth factor (IGF) system. Cleavage of their only known substrates, a subset of IGF binding proteins (IGFBPs), releases bioactive IGFI and IGFII, thus promoting IGF signaling. Stanniocalcin-1 and -2 (STC1 and STC2) are potent pappalysin inhibitors, completing the STC-PAPP-A-IGFBP-IGF axis. Utilizing homology searches and phylogenetic analyses, we examined the occurrence of pappalysins in the animal kingdom and their functional conservation. This revealed the extensive presence of pappalysins across metazoans, as well as the presence of 3 pappalysins: PAPP-A, PAPP-A2, and a third group of invertebrate pappalysins, which we name invertebrate PAPP-A (invPAPP-A). We show that PAPP-A and PAPP-A2 arose by duplication during early vertebrate evolution. Despite significant evolutionary distance, the domain architecture of the metazoan pappalysins is completely conserved, and several functional domains and motifs are highly conserved across all pappalysins. However, invPAPP-A exists outside the context of IGFBPs, suggesting that the animal pappalysins may have substrates beyond the IGFBPs for PAPP-A and PAPP-A2 that remain to be discovered. Since PAPP-A is an emerging drug target, it is important to understand potential involvement in regulatory systems other than the IGF system, which might be affected upon targeting of PAPP-A.

KW - IGF

KW - IGFBP

KW - PAPP-A

KW - PAPP-A2

KW - pappalysin phylogeny

KW - proteinase

UR - https://www.scopus.com/pages/publications/105000664968

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DO - 10.1093/gbe/evaf042

M3 - Journal article

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AN - SCOPUS:105000664968

SN - 1759-6653

VL - 17

JO - Genome Biology and Evolution

JF - Genome Biology and Evolution

IS - 3

M1 - evaf042

ER -

The Proteinase PAPP-A has Deep Evolutionary Roots Outside of the IGF System

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Keywords

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