Pregnancy-associated plasma protein-A (PAPP-A) modulates early developmental rate in zebrafish independent of its proteolytic activity

Kasper Kjær-Sørensen, Ditte Høyer Engholm, Hiroyasu Kamei, Maria Grymer Metz Mørch, Anisette O Kristensen, Jianfeng Zhou, Cheryl A. Conover, Cunming Duan, Claus Oxvig

    Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

    25 Citationer (Scopus)

    Abstract

    Pregnancy-associated plasma protein-A (PAPP-A) is a large metalloproteinase specifically cleaving IGF binding proteins, causing increased IGF bioavailability and hence local regulation of IGF receptor activation. We have identified two highly conserved zebrafish homologs of the human PAPP-A gene. Expression of zebrafish Papp-a, one of the two paralogs, begins during gastrulation and persists throughout the first week of development, and analyses demonstrate highly conserved patterns of expression between adult zebrafish, humans, and mice. We show that the specific knockdown of zebrafish papp-a limits the developmental rate beginning during gastrulation without affecting the normal patterning of the embryo. This phenotype is different from those resulting from deficiency of Igf receptor or ligand in zebrafish, suggesting a function of Papp-a outside the Igf system. Biochemical analysis of recombinant zebrafish Papp-a demonstrates conservation of proteolytic activity, specificity, and intrinsic regulatory mechanism. However, in vitro transcribed mRNA, which encodes a proteolytically inactive Papp-a mutant, recues the papp-a knockdown phenotype as efficient as wild-type Papp-a. Thus, the developmental phenotype of papp-a knockdown is not a consequence of lacking Papp-a proteolytic activity. We conclude that Papp-a possesses biological functions independent of its proteolytic activity. Our data represent the first evidence for a non-proteolytic function of PAPP-A.
    OriginalsprogEngelsk
    TidsskriftJournal of Biological Chemistry
    Vol/bind288
    Sider (fra-til)9982-9992
    Antal sider11
    ISSN0021-9258
    DOI
    StatusUdgivet - apr. 2013

    Emneord

    • zebrafisk
    • PAPP-A
    • proteolyse

    Fingeraftryk

    Dyk ned i forskningsemnerne om 'Pregnancy-associated plasma protein-A (PAPP-A) modulates early developmental rate in zebrafish independent of its proteolytic activity'. Sammen danner de et unikt fingeraftryk.

    Citationsformater