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Sorting nexin 9 (SNX9) regulates levels of the transmembrane ADAM9 at the cell surface

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DOI

  • Kasper J Mygind, From the Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark and.
  • ,
  • Theresa Störiko, From the Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark and.
  • ,
  • Marie L Freiberg, From the Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark and.
  • ,
  • Jacob Samsøe-Petersen, From the Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark and.
  • ,
  • Jeanette Schwarz, From the Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark and.
  • ,
  • Olav M Andersen
  • Marie Kveiborg, From the Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark and marie.kveiborg@sund.ku.dk.

ADAM9 is an active member of the family of transmembrane ADAMs (a disintegrin and metalloproteases). It plays a role in processes such as bone formation and retinal neovascularization, and importantly, its expression in human cancers correlates with disease stage and poor prognosis. Functionally, ADAM9 can cleave several transmembrane proteins, thereby shedding their ectodomains from the cell surface. Moreover, ADAM9 regulates cell behavior by binding cell-surface receptors such as integrin and membrane-type matrix metalloproteases. Because these functions are mainly restricted to the cell surface, understanding the mechanisms regulating ADAM9 localization and activity at this site is highly important. To this end, we here investigated how intracellular trafficking regulates ADAM9 availability at the cell surface. We found that ADAM9 undergoes constitutive clathrin-dependent internalization and subsequent degradation or recycling to the plasma membrane. We confirmed previous findings of an interaction between ADAM9 and the intracellular sorting protein, sorting nexin 9 (SNX9), as well as its close homolog SNX18. Knockdown of either SNX9 or SNX18 had no apparent effects on ADAM9 internalization or recycling. However, double knockdown of SNX9 and SNX18 decreased ADAM9 internalization significantly, demonstrating a redundant role in this process. Moreover, SNX9 knockdown revealed a nonredundant effect on overall ADAM9 protein levels, resulting in increased ADAM9 levels at the cell surface, and a corresponding increase in the shedding of Ephrin receptor B4, a well-known ADAM9 substrate. Together, our findings demonstrate that intracellular SNX9-mediated trafficking constitutes an important ADAM9 regulatory pathway.

OriginalsprogEngelsk
TidsskriftJournal of Biological Chemistry
Vol/bind293
Nummer21
Sider (fra-til)8077-8088
Antal sider12
ISSN0021-9258
DOI
StatusUdgivet - 25 maj 2018

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