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Title: Hepatocyte growth factor regulated tyrosine kinase substrate in the peripheral development and function of B-cells

Abstract

Highlights: •ESCRT-0 protein regulates the development of peripheral B-cells. •BCR expression on cell surface should be controlled by the endosomal-sorting system. •Hrs plays important roles in responsiveness to Ag stimulation in B lymphocytes. -- Abstract: Hepatocyte growth factor (HGF)-regulated tyrosine kinase substrate (Hrs) is a vesicular sorting protein that functions as one of the endosomal-sorting proteins required for transport (ESCRT). Hrs, which binds to ubiquitinated proteins through its ubiquitin-interacting motif (UIM), contributes to the lysosomal transport and degradation of ubiquitinated membrane proteins. However, little is known about the relationship between B-cell functions and ESCRT proteins in vivo. Here we examined the immunological roles of Hrs in B-cell development and functions using B-cell-specific Hrs-deficient (Hrs{sup flox/flox};mb1{sup cre/+}:Hrs-cKO) mice, which were generated using a cre-LoxP recombination system. Hrs deficiency in B-cells significantly reduced T-cell-dependent antibody production in vivo and impaired the proliferation of B-cells treated in vitro with an anti-IgM monoclonal antibody but not with LPS. Although early development of B-cells in the bone marrow was normal in Hrs-cKO mice, there was a significant decrease in the number of the peripheral transitional B-cells and marginal zone B-cells in the spleen of Hrs-cKO mice. These results indicate that Hrs plays important roles duringmore » peripheral development and physiological functions of B lymphocytes.« less

Authors:
 [1];  [2];  [1];  [1];  [3]; ;  [1]; ;  [4];  [5];  [6];  [4];  [3]
  1. Department of Pharmacy, Iwaki Meisei University, 5-5-1 Chuodai Iino, Iwaki, Fukushima 970-8551 (Japan)
  2. (Japan)
  3. Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575 (Japan)
  4. Division of Immunology, Miyagi Cancer Research Institute, 47-1 Nodayama, Medeshima-Shiode, Natori 981-1293 (Japan)
  5. Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575 (Japan)
  6. Institute for Animal Experimentation, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575 (Japan)
Publication Date:
OSTI Identifier:
22242253
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 443; Journal Issue: 2; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BONE MARROW; GROWTH FACTORS; LYMPHOCYTES; MEMBRANE PROTEINS; MICE; MONOCLONAL ANTIBODIES; TYROSINE

Citation Formats

Nagata, Takayuki, Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Murata, Kazuko, E-mail: murata-k@iwakimu.ac.jp, Murata, Ryo, Sun, Shu-lan, Saito, Yutaro, Yamaga, Shuhei, Tanaka, Nobuyuki, Tamai, Keiichi, Moriya, Kunihiko, Kasai, Noriyuki, Sugamura, Kazuo, and Ishii, Naoto. Hepatocyte growth factor regulated tyrosine kinase substrate in the peripheral development and function of B-cells. United States: N. p., 2014. Web. doi:10.1016/J.BBRC.2013.11.029.
Nagata, Takayuki, Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Murata, Kazuko, E-mail: murata-k@iwakimu.ac.jp, Murata, Ryo, Sun, Shu-lan, Saito, Yutaro, Yamaga, Shuhei, Tanaka, Nobuyuki, Tamai, Keiichi, Moriya, Kunihiko, Kasai, Noriyuki, Sugamura, Kazuo, & Ishii, Naoto. Hepatocyte growth factor regulated tyrosine kinase substrate in the peripheral development and function of B-cells. United States. doi:10.1016/J.BBRC.2013.11.029.
Nagata, Takayuki, Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Murata, Kazuko, E-mail: murata-k@iwakimu.ac.jp, Murata, Ryo, Sun, Shu-lan, Saito, Yutaro, Yamaga, Shuhei, Tanaka, Nobuyuki, Tamai, Keiichi, Moriya, Kunihiko, Kasai, Noriyuki, Sugamura, Kazuo, and Ishii, Naoto. Fri . "Hepatocyte growth factor regulated tyrosine kinase substrate in the peripheral development and function of B-cells". United States. doi:10.1016/J.BBRC.2013.11.029.
@article{osti_22242253,
title = {Hepatocyte growth factor regulated tyrosine kinase substrate in the peripheral development and function of B-cells},
author = {Nagata, Takayuki and Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575 and Murata, Kazuko, E-mail: murata-k@iwakimu.ac.jp and Murata, Ryo and Sun, Shu-lan and Saito, Yutaro and Yamaga, Shuhei and Tanaka, Nobuyuki and Tamai, Keiichi and Moriya, Kunihiko and Kasai, Noriyuki and Sugamura, Kazuo and Ishii, Naoto},
abstractNote = {Highlights: •ESCRT-0 protein regulates the development of peripheral B-cells. •BCR expression on cell surface should be controlled by the endosomal-sorting system. •Hrs plays important roles in responsiveness to Ag stimulation in B lymphocytes. -- Abstract: Hepatocyte growth factor (HGF)-regulated tyrosine kinase substrate (Hrs) is a vesicular sorting protein that functions as one of the endosomal-sorting proteins required for transport (ESCRT). Hrs, which binds to ubiquitinated proteins through its ubiquitin-interacting motif (UIM), contributes to the lysosomal transport and degradation of ubiquitinated membrane proteins. However, little is known about the relationship between B-cell functions and ESCRT proteins in vivo. Here we examined the immunological roles of Hrs in B-cell development and functions using B-cell-specific Hrs-deficient (Hrs{sup flox/flox};mb1{sup cre/+}:Hrs-cKO) mice, which were generated using a cre-LoxP recombination system. Hrs deficiency in B-cells significantly reduced T-cell-dependent antibody production in vivo and impaired the proliferation of B-cells treated in vitro with an anti-IgM monoclonal antibody but not with LPS. Although early development of B-cells in the bone marrow was normal in Hrs-cKO mice, there was a significant decrease in the number of the peripheral transitional B-cells and marginal zone B-cells in the spleen of Hrs-cKO mice. These results indicate that Hrs plays important roles during peripheral development and physiological functions of B lymphocytes.},
doi = {10.1016/J.BBRC.2013.11.029},
journal = {Biochemical and Biophysical Research Communications},
number = 2,
volume = 443,
place = {United States},
year = {Fri Jan 10 00:00:00 EST 2014},
month = {Fri Jan 10 00:00:00 EST 2014}
}
  • Research highlights: {yields} CREB is a regulatory target for the protein kinase Akt/PKB in pancreatic duct cells. {yields} Activation of the PI3K/AKT/CREB pathway plays a critical role in the HGF-mediated differentiation of pancreatic duct cells in vivo. {yields} CREB was causally linked to the expression of transcription factors during PDEC differentiation induced by HGF. -- Abstract: We have previously reported that the PI3K/Akt signaling pathway is involved in hepatocyte growth factor (HGF)-induced differentiation of adult rat pancreatic ductal epithelial cells (PDECs) into islet {beta}-cells in vitro. The transcription factor CREB is one of the downstream key effectors of the PI3K/Aktmore » signaling pathway. Recent studies showing that CREB is required for the survival of certain cell types prompted us to examine whether CREB is a nuclear target for activation via the HGF-dependent Ser/Thr kinase Akt/PKB in the differentiation of pancreatic duct cell into islet {beta}-cells. In this study, we first attempted to examine whether HGF modulates the Akt-dependent activation of target gene CREB and then investigated whether CREB activity affects the differentiation of HGF-induced PDECs. Finally, we studied the role of CREB in modulating the expression of transcription factors in PDECs during the differentiation of HGF-induced PDECs. Our results demonstrated that CREB is a regulatory target for the protein kinase Akt/PKB in the differentiation of pancreatic ductal cells into islet {beta}-cells mediated by HGF.« less
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