HAI-2 stabilizes, inhibits and regulates SEA-cleavage-dependent secretory transport of matriptase

Annika Weile Nonboe; Oliver Krigslund; Christoffer Søndergård; Signe Skovbjerg Thomsen; Stine Friis; Martin Nybo Andersen; Vincent Ellis; Makiko Kawaguchi; Hiroaki Kataoka; Thomas H. Bugge; Lotte Vogel

doi:10.1111/tra.12482

HAI-2 stabilizes, inhibits and regulates SEA-cleavage-dependent secretory transport of matriptase

Annika Weile Nonboe, Oliver Krigslund, Christoffer Søndergård, Signe Skovbjerg Thomsen, Stine Friis, Martin Nybo Andersen, Vincent Ellis, Makiko Kawaguchi, Hiroaki Kataoka, Thomas H. Bugge, Lotte Vogel

15 Citations (Scopus)

Abstract

It has recently been shown that hepatocyte growth factor activator inhibitor-2 (HAI-2) is able to suppress carcinogenesis induced by overexpression of matriptase, as well as cause regression of individual established tumors in a mouse model system. However, the role of HAI-2 is poorly understood. In this study, we describe 3 mutations in the binding loop of the HAI-2 Kunitz domain 1 (K42N, C47F and R48L) that cause a delay in the SEA domain cleavage of matriptase, leading to accumulation of non-SEA domain cleaved matriptase in the endoplasmic reticulum (ER). We suggest that, like other known SEA domains, the matriptase SEA domain auto-cleaves and reflects that correct oligomerization, maturation, and/or folding has been obtained. Our results suggest that the HAI-2 Kunitz domain 1 mutants influence the flux of matriptase to the plasma membrane by affecting the oligomerization, maturation and/or folding of matriptase, and as a result the SEA domain cleavage of matriptase. Two of the HAI-2 Kunitz domain 1 mutants investigated (C47F, R48L and C47F/R48L) also displayed a reduced ability to proteolytically silence matriptase. Hence, HAI-2 separately stabilizes matriptase, regulates the secretory transport, possibly via maturation/oligomerization and inhibits the proteolytic activity of matriptase in the ER, and possible throughout the secretory pathway.

Original language	English
Journal	Traffic
Volume	18
Issue number	6
Pages (from-to)	378-391
Number of pages	14
ISSN	1398-9219
DOIs	https://doi.org/10.1111/tra.12482
Publication status	Published - Jun 2017

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@article{4a7d11e8e1364ff2a3d0a11c7acc7f41,

title = "HAI-2 stabilizes, inhibits and regulates SEA-cleavage-dependent secretory transport of matriptase",

abstract = "It has recently been shown that hepatocyte growth factor activator inhibitor-2 (HAI-2) is able to suppress carcinogenesis induced by overexpression of matriptase, as well as cause regression of individual established tumors in a mouse model system. However, the role of HAI-2 is poorly understood. In this study, we describe 3 mutations in the binding loop of the HAI-2 Kunitz domain 1 (K42N, C47F and R48L) that cause a delay in the SEA domain cleavage of matriptase, leading to accumulation of non-SEA domain cleaved matriptase in the endoplasmic reticulum (ER). We suggest that, like other known SEA domains, the matriptase SEA domain auto-cleaves and reflects that correct oligomerization, maturation, and/or folding has been obtained. Our results suggest that the HAI-2 Kunitz domain 1 mutants influence the flux of matriptase to the plasma membrane by affecting the oligomerization, maturation and/or folding of matriptase, and as a result the SEA domain cleavage of matriptase. Two of the HAI-2 Kunitz domain 1 mutants investigated (C47F, R48L and C47F/R48L) also displayed a reduced ability to proteolytically silence matriptase. Hence, HAI-2 separately stabilizes matriptase, regulates the secretory transport, possibly via maturation/oligomerization and inhibits the proteolytic activity of matriptase in the ER, and possible throughout the secretory pathway.",

author = "Nonboe, {Annika Weile} and Oliver Krigslund and Christoffer S{\o}nderg{\aa}rd and Thomsen, {Signe Skovbjerg} and Stine Friis and Andersen, {Martin Nybo} and Vincent Ellis and Makiko Kawaguchi and Hiroaki Kataoka and Bugge, {Thomas H.} and Lotte Vogel",

note = "{\textcopyright} 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.",

year = "2017",

month = jun,

doi = "10.1111/tra.12482",

language = "English",

volume = "18",

pages = "378--391",

journal = "Traffic",

issn = "1398-9219",

publisher = "Wiley-Blackwell",

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T1 - HAI-2 stabilizes, inhibits and regulates SEA-cleavage-dependent secretory transport of matriptase

AU - Nonboe, Annika Weile

AU - Krigslund, Oliver

AU - Søndergård, Christoffer

AU - Thomsen, Signe Skovbjerg

AU - Friis, Stine

AU - Andersen, Martin Nybo

AU - Ellis, Vincent

AU - Kawaguchi, Makiko

AU - Kataoka, Hiroaki

AU - Bugge, Thomas H.

AU - Vogel, Lotte

PY - 2017/6

Y1 - 2017/6

N2 - It has recently been shown that hepatocyte growth factor activator inhibitor-2 (HAI-2) is able to suppress carcinogenesis induced by overexpression of matriptase, as well as cause regression of individual established tumors in a mouse model system. However, the role of HAI-2 is poorly understood. In this study, we describe 3 mutations in the binding loop of the HAI-2 Kunitz domain 1 (K42N, C47F and R48L) that cause a delay in the SEA domain cleavage of matriptase, leading to accumulation of non-SEA domain cleaved matriptase in the endoplasmic reticulum (ER). We suggest that, like other known SEA domains, the matriptase SEA domain auto-cleaves and reflects that correct oligomerization, maturation, and/or folding has been obtained. Our results suggest that the HAI-2 Kunitz domain 1 mutants influence the flux of matriptase to the plasma membrane by affecting the oligomerization, maturation and/or folding of matriptase, and as a result the SEA domain cleavage of matriptase. Two of the HAI-2 Kunitz domain 1 mutants investigated (C47F, R48L and C47F/R48L) also displayed a reduced ability to proteolytically silence matriptase. Hence, HAI-2 separately stabilizes matriptase, regulates the secretory transport, possibly via maturation/oligomerization and inhibits the proteolytic activity of matriptase in the ER, and possible throughout the secretory pathway.

AB - It has recently been shown that hepatocyte growth factor activator inhibitor-2 (HAI-2) is able to suppress carcinogenesis induced by overexpression of matriptase, as well as cause regression of individual established tumors in a mouse model system. However, the role of HAI-2 is poorly understood. In this study, we describe 3 mutations in the binding loop of the HAI-2 Kunitz domain 1 (K42N, C47F and R48L) that cause a delay in the SEA domain cleavage of matriptase, leading to accumulation of non-SEA domain cleaved matriptase in the endoplasmic reticulum (ER). We suggest that, like other known SEA domains, the matriptase SEA domain auto-cleaves and reflects that correct oligomerization, maturation, and/or folding has been obtained. Our results suggest that the HAI-2 Kunitz domain 1 mutants influence the flux of matriptase to the plasma membrane by affecting the oligomerization, maturation and/or folding of matriptase, and as a result the SEA domain cleavage of matriptase. Two of the HAI-2 Kunitz domain 1 mutants investigated (C47F, R48L and C47F/R48L) also displayed a reduced ability to proteolytically silence matriptase. Hence, HAI-2 separately stabilizes matriptase, regulates the secretory transport, possibly via maturation/oligomerization and inhibits the proteolytic activity of matriptase in the ER, and possible throughout the secretory pathway.

U2 - 10.1111/tra.12482

DO - 10.1111/tra.12482

M3 - Journal article

C2 - 28371047

SN - 1398-9219

VL - 18

SP - 378

EP - 391

JO - Traffic

JF - Traffic

IS - 6

ER -

HAI-2 stabilizes, inhibits and regulates SEA-cleavage-dependent secretory transport of matriptase

Abstract

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