PMID- 25842366
OWN - NLM
STAT- MEDLINE
DCOM- 20160225
LR  - 20201209
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Print)
IS  - 0002-9440 (Linking)
VI  - 185
IP  - 6
DP  - 2015 Jun
TI  - Hepatocyte growth factor activator inhibitor type 1 maintains the assembly of 
      keratin into desmosomes in keratinocytes by regulating protease-activated 
      receptor 2-dependent p38 signaling.
PG  - 1610-23
LID - S0002-9440(15)00141-8 [pii]
LID - 10.1016/j.ajpath.2015.02.009 [doi]
AB  - Hepatocyte growth factor activator inhibitor type 1 (HAI-1; official symbol 
      SPINT1) is a membrane-associated serine proteinase inhibitor abundantly expressed 
      in epithelial tissues. Genetically engineered mouse models demonstrated that 
      HAI-1 is critical for epidermal function, possibly through direct and indirect 
      regulation of cell surface proteases, such as matriptase and prostasin. To obtain 
      a better understanding of the role of HAI-1 in maintaining epidermal integrity, 
      we performed ultrastructural analysis of Spint1-deleted mouse epidermis and 
      organotypic culture of an HAI-1 knockdown (KD) human keratinocyte cell line, 
      HaCaT. We found that the aggregation of tonofilaments to desmosomes was 
      significantly reduced in HAI-1-deficient mouse epidermis with decreased desmosome 
      number. Similar findings were observed in HAI-1 KD HaCaT organotypic cultures. 
      Immunoblot and immunohistochemical analyses revealed that p38 mitogen-activated 
      protein kinase was activated in response to HAI-1 insufficiency. Treatment of 
      HAI-1 KD HaCaT cells with a p38 inhibitor abrogated the above-observed 
      ultrastructural abnormalities. The activation of p38 induced by the loss of HAI-1 
      likely resulted from enhanced signaling of protease-activated receptor-2 (PAR-2), 
      because its silencing abrogated the enhanced activation of p38. Consequently, 
      treatment of HAI-1 KD HaCaT cells with a serine protease inhibitor, aprotinin, or 
      PAR-2 antagonist alleviated the abnormal ultrastructural phenotype in organotypic 
      culture. These results suggest that HAI-1 may have a critical role in maintaining 
      normal keratinocyte morphology through regulation of PAR-2-dependent p38 
      mitogen-activated protein kinase signaling.
CI  - Copyright (c) 2015 American Society for Investigative Pathology. Published by 
      Elsevier Inc. All rights reserved.
FAU - Kawaguchi, Makiko
AU  - Kawaguchi M
AD  - Section of Oncopathology and Regenerative Biology, Department of Pathology, 
      Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
FAU - Kanemaru, Ai
AU  - Kanemaru A
AD  - Section of Oncopathology and Regenerative Biology, Department of Pathology, 
      Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
FAU - Sawaguchi, Akira
AU  - Sawaguchi A
AD  - Section of Ultrastructural Cell Biology, Department of Anatomy, Faculty of 
      Medicine, University of Miyazaki, Miyazaki, Japan.
FAU - Yamamoto, Koji
AU  - Yamamoto K
AD  - Section of Oncopathology and Regenerative Biology, Department of Pathology, 
      Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Department of Oral 
      and Maxillofacial Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, 
      Japan.
FAU - Baba, Takashi
AU  - Baba T
AD  - Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of 
      Miyazaki, Miyazaki, Japan.
FAU - Lin, Chen-Yong
AU  - Lin CY
AD  - Department of Oncology, Lambardi Comprehensive Cancer Centre, Georgetown 
      University, School of Medicine, Washington, District of Columbia.
FAU - Johnson, Michael D
AU  - Johnson MD
AD  - Department of Oncology, Lambardi Comprehensive Cancer Centre, Georgetown 
      University, School of Medicine, Washington, District of Columbia.
FAU - Fukushima, Tsuyoshi
AU  - Fukushima T
AD  - Section of Oncopathology and Regenerative Biology, Department of Pathology, 
      Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
FAU - Kataoka, Hiroaki
AU  - Kataoka H
AD  - Section of Oncopathology and Regenerative Biology, Department of Pathology, 
      Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. Electronic address: 
      mejina@med.miyazaki-u.ac.jp.
LA  - eng
GR  - P30 CA051008/CA/NCI NIH HHS/United States
GR  - R01 CA123223/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150401
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Proteinase Inhibitory Proteins, Secretory)
RN  - 0 (Receptor, PAR-2)
RN  - 0 (Spint1 protein, mouse)
RN  - 68238-35-7 (Keratins)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Desmosomes/*metabolism
MH  - Gene Silencing
MH  - Humans
MH  - Keratinocytes/*metabolism
MH  - Keratins/*metabolism
MH  - Membrane Glycoproteins/*metabolism
MH  - Mice
MH  - Proteinase Inhibitory Proteins, Secretory
MH  - Receptor, PAR-2/*metabolism
MH  - Signal Transduction/*physiology
MH  - Skin/metabolism
MH  - p38 Mitogen-Activated Protein Kinases/*metabolism
PMC - PMC5707200
EDAT- 2015/04/07 06:00
MHDA- 2016/02/26 06:00
PMCR- 2016/06/01
CRDT- 2015/04/06 06:00
PHST- 2014/09/03 00:00 [received]
PHST- 2015/01/26 00:00 [revised]
PHST- 2015/02/03 00:00 [accepted]
PHST- 2015/04/06 06:00 [entrez]
PHST- 2015/04/07 06:00 [pubmed]
PHST- 2016/02/26 06:00 [medline]
PHST- 2016/06/01 00:00 [pmc-release]
AID - S0002-9440(15)00141-8 [pii]
AID - 10.1016/j.ajpath.2015.02.009 [doi]
PST - ppublish
SO  - Am J Pathol. 2015 Jun;185(6):1610-23. doi: 10.1016/j.ajpath.2015.02.009. Epub 
      2015 Apr 1.