MT1-MMP and ADAM10/17 exhibit a remarkable overlap of shedding properties
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MT1-MMP and ADAM10/17 exhibit a remarkable overlap of shedding properties. / Werny, Ludwig; Grogro, Antonia; Bickenbach, Kira; Bülck, Cynthia; Armbrust, Fred; Koudelka, Tomas; Pathak, Kriti; Scharfenberg, Franka; Sammel, Martin; Sheikhouny, Farah; Tholey, Andreas; Linder, Stefan; Becker-Pauly, Christoph.
in: FEBS J, Jahrgang 290, Nr. 1, 01.2023, S. 93-111.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - MT1-MMP and ADAM10/17 exhibit a remarkable overlap of shedding properties
AU - Werny, Ludwig
AU - Grogro, Antonia
AU - Bickenbach, Kira
AU - Bülck, Cynthia
AU - Armbrust, Fred
AU - Koudelka, Tomas
AU - Pathak, Kriti
AU - Scharfenberg, Franka
AU - Sammel, Martin
AU - Sheikhouny, Farah
AU - Tholey, Andreas
AU - Linder, Stefan
AU - Becker-Pauly, Christoph
N1 - © 2022 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
PY - 2023/1
Y1 - 2023/1
N2 - Membrane-type-I matrix metalloproteinase (MT1-MMP) is one of six human membrane-bound MMPs and is responsible for extracellular matrix remodelling by degrading several substrates like fibrillar collagens, including types I-III, or fibronectin. Moreover, MT1-MMP was described as a key player in cancer progression and it is involved in various inflammatory processes, as well as in the pathogenesis of Alzheimer's disease (AD). The membrane-tethered metalloprotease meprin β as well as a disintegrin and metalloproteinase 10 (ADAM10) and ADAM17 are also associated with these diseases. Interestingly, meprin β, ADAM10/17 and MT1-MMP also have a shared substrate pool including the interleukin-6 receptor and the amyloid precursor protein. We investigated the interaction of these proteases, focusing on a possible connection between MT1-MMP and meprin β, to elucidate the potential mutual regulations of both enzymes. Herein, we show that besides ADAM10/17, MT1-MMP is also able to shed meprin β from the plasma membrane, leading to the release of soluble meprin β. Mass spectrometry-based cleavage site analysis revealed that the cleavage of meprin β by all three proteases occurs between Pro602 and Ser603 , N-terminal of the EGF-like domain. Furthermore, only inactive human pro-meprin β is shed by MT1-MMP, which is again in accordance with the shedding capability observed for ADAM10/17. Vice versa, meprin β also appears to shed MT1-MMP, indicating a complex regulatory network. Further studies will elucidate this well-orchestrated proteolytic web under distinct conditions in health and disease and will possibly show whether the loss of one of the above-mentioned sheddases can be compensated by the other enzymes.
AB - Membrane-type-I matrix metalloproteinase (MT1-MMP) is one of six human membrane-bound MMPs and is responsible for extracellular matrix remodelling by degrading several substrates like fibrillar collagens, including types I-III, or fibronectin. Moreover, MT1-MMP was described as a key player in cancer progression and it is involved in various inflammatory processes, as well as in the pathogenesis of Alzheimer's disease (AD). The membrane-tethered metalloprotease meprin β as well as a disintegrin and metalloproteinase 10 (ADAM10) and ADAM17 are also associated with these diseases. Interestingly, meprin β, ADAM10/17 and MT1-MMP also have a shared substrate pool including the interleukin-6 receptor and the amyloid precursor protein. We investigated the interaction of these proteases, focusing on a possible connection between MT1-MMP and meprin β, to elucidate the potential mutual regulations of both enzymes. Herein, we show that besides ADAM10/17, MT1-MMP is also able to shed meprin β from the plasma membrane, leading to the release of soluble meprin β. Mass spectrometry-based cleavage site analysis revealed that the cleavage of meprin β by all three proteases occurs between Pro602 and Ser603 , N-terminal of the EGF-like domain. Furthermore, only inactive human pro-meprin β is shed by MT1-MMP, which is again in accordance with the shedding capability observed for ADAM10/17. Vice versa, meprin β also appears to shed MT1-MMP, indicating a complex regulatory network. Further studies will elucidate this well-orchestrated proteolytic web under distinct conditions in health and disease and will possibly show whether the loss of one of the above-mentioned sheddases can be compensated by the other enzymes.
U2 - 10.1111/febs.16586
DO - 10.1111/febs.16586
M3 - SCORING: Journal article
C2 - 35944080
VL - 290
SP - 93
EP - 111
JO - FEBS J
JF - FEBS J
SN - 1742-464X
IS - 1
ER -