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

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

doi:10.1111/tra.12482

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

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

School of Biological Sciences

Research output: Contribution to journal › Article › peer-review

21 Citations (Scopus)

26 Downloads (Pure)

Abstract

It has recently been shown that 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 the present study we describe three 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 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, 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
Pages (from-to)	378–391
Number of pages	14
Journal	Traffic
Volume	18
Issue number	6
Early online date	28 Mar 2017
DOIs	https://doi.org/10.1111/tra.12482
Publication status	Published - Jun 2017

Keywords

matriptase
HAI-2
HAI-1
SEA domain cleavage
secretory transport
chromogenic activity

Access to Document

10.1111/tra.12482

Accepted manuscriptAccepted author manuscript, 1.9 MB

http://doi.wiley.com/10.1111/tra.12482

Cite this

@article{b80d190e17574a89b09d91830600c5c7,

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

abstract = "It has recently been shown that 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 the present study we describe three 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 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, 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.",

keywords = "matriptase, HAI-2, HAI-1, SEA domain cleavage, secretory transport, chromogenic activity",

author = "Nonboe, {Annika W.} and Oliver Krigslund and Christoffer Soendergaard and Signe Skovbjerg and Stine Friis and Andersen, {Martin Nybo} and Vincent Ellis and Makiko Kawaguchi and Hiroaki Kataoka and Bugge, {Thomas H.} and Vogel, {Lotte K.}",

year = "2017",

month = jun,

doi = "10.1111/tra.12482",

language = "English",

volume = "18",

pages = "378–391",

journal = "Traffic",

issn = "1398-9219",

publisher = "Blackwell Munksgaard",

number = "6",

}

HAI-2 stabilizes, inhibits, and regulates SEA-cleavage-dependent secretory transport of matriptase. / Nonboe, Annika W.; Krigslund, Oliver; Soendergaard, Christoffer; Skovbjerg, Signe; Friis, Stine; Andersen, Martin Nybo; Ellis, Vincent; Kawaguchi, Makiko; Kataoka, Hiroaki; Bugge, Thomas H.; Vogel, Lotte K.

In: Traffic, Vol. 18, No. 6, 06.2017, p. 378–391.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

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

AU - Nonboe, Annika W.

AU - Krigslund, Oliver

AU - Soendergaard, Christoffer

AU - Skovbjerg, Signe

AU - Friis, Stine

AU - Andersen, Martin Nybo

AU - Ellis, Vincent

AU - Kawaguchi, Makiko

AU - Kataoka, Hiroaki

AU - Bugge, Thomas H.

AU - Vogel, Lotte K.

PY - 2017/6

Y1 - 2017/6

N2 - It has recently been shown that 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 the present study we describe three 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 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, 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 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 the present study we describe three 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 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, 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.

KW - matriptase

KW - HAI-2

KW - HAI-1

KW - SEA domain cleavage

KW - secretory transport

KW - chromogenic activity

U2 - 10.1111/tra.12482

DO - 10.1111/tra.12482

M3 - Article

VL - 18

SP - 378

EP - 391

JO - Traffic

JF - Traffic

SN - 1398-9219

IS - 6

ER -