The extremely conserved C-terminal region of Reelin is not necessary for secretion but is required for efficient activation of downstream signaling

Yoshimi Nakano, Takao Kohno, Terumasa Hibi, Shiori Kohno, Atsushi Baba, Katsuhiko Mikoshiba, Kazunori Nakajima, Mitsuharu Hattori

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Reelin is a very large secreted glycoprotein essential for correct development of the mammalian brain. It is also implicated in higher functions and diseases of human brain. However, whether or not secretion of Reelin is regulated and how Reelin transmits signals remain largely unknown. Reelin protein is composed of an N-terminal F-spondin-like domain, Reelin repeats, and a short and highly basic C-terminal region (CTR). The primary sequence of CTR is almost completely conserved among vertebrates except fishes, indicating its importance. A prevailing idea regarding the function of CTR is that it is required for the secretion of Reelin, although this remains unproven. Here we aimed to clarify the function of Reelin CTR. Neither deleting most of CTR nor replacing CTR with unrelated amino acids affected secretion efficiency, indicating that CTR is not absolutely required for the secretion of Reelin. We also found that Reelin mutants without CTR were less potent in activating the downstream signaling in cortical neurons. Although these mutants were able to bind to the Reelin receptor ectodomain as efficiently as wild-type Reelin, quite interestingly, their ability to bind to the isolated cell membrane bearing Reelin receptors or receptor-expressing cells (including cortical neurons) was much weaker than that of wild-type Reelin. Therefore, it is concluded that the CTR of Reelin is not essential for its secretion but is required for efficient activation of downstream signaling events, presumably via binding to an unidentified "coreceptor" molecule(s) on the cell membrane.

Original languageEnglish
Pages (from-to)20544-20552
Number of pages9
JournalJournal of Biological Chemistry
Volume282
Issue number28
DOIs
Publication statusPublished - 2007 Jul 13

Fingerprint

Chemical activation
Cell Membrane
Cell membranes
Neurons
Brain
Brain Diseases
Bearings (structural)
Vertebrates
Glycoproteins
Fishes
Amino Acids
Fish
Molecules
reelin receptor
reelin protein

ASJC Scopus subject areas

  • Biochemistry

Cite this

The extremely conserved C-terminal region of Reelin is not necessary for secretion but is required for efficient activation of downstream signaling. / Nakano, Yoshimi; Kohno, Takao; Hibi, Terumasa; Kohno, Shiori; Baba, Atsushi; Mikoshiba, Katsuhiko; Nakajima, Kazunori; Hattori, Mitsuharu.

In: Journal of Biological Chemistry, Vol. 282, No. 28, 13.07.2007, p. 20544-20552.

Research output: Contribution to journalArticle

Nakano, Yoshimi ; Kohno, Takao ; Hibi, Terumasa ; Kohno, Shiori ; Baba, Atsushi ; Mikoshiba, Katsuhiko ; Nakajima, Kazunori ; Hattori, Mitsuharu. / The extremely conserved C-terminal region of Reelin is not necessary for secretion but is required for efficient activation of downstream signaling. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 28. pp. 20544-20552.
@article{8f5dac6296444675b3e62dc2d1b2ccb3,
title = "The extremely conserved C-terminal region of Reelin is not necessary for secretion but is required for efficient activation of downstream signaling",
abstract = "Reelin is a very large secreted glycoprotein essential for correct development of the mammalian brain. It is also implicated in higher functions and diseases of human brain. However, whether or not secretion of Reelin is regulated and how Reelin transmits signals remain largely unknown. Reelin protein is composed of an N-terminal F-spondin-like domain, Reelin repeats, and a short and highly basic C-terminal region (CTR). The primary sequence of CTR is almost completely conserved among vertebrates except fishes, indicating its importance. A prevailing idea regarding the function of CTR is that it is required for the secretion of Reelin, although this remains unproven. Here we aimed to clarify the function of Reelin CTR. Neither deleting most of CTR nor replacing CTR with unrelated amino acids affected secretion efficiency, indicating that CTR is not absolutely required for the secretion of Reelin. We also found that Reelin mutants without CTR were less potent in activating the downstream signaling in cortical neurons. Although these mutants were able to bind to the Reelin receptor ectodomain as efficiently as wild-type Reelin, quite interestingly, their ability to bind to the isolated cell membrane bearing Reelin receptors or receptor-expressing cells (including cortical neurons) was much weaker than that of wild-type Reelin. Therefore, it is concluded that the CTR of Reelin is not essential for its secretion but is required for efficient activation of downstream signaling events, presumably via binding to an unidentified {"}coreceptor{"} molecule(s) on the cell membrane.",
author = "Yoshimi Nakano and Takao Kohno and Terumasa Hibi and Shiori Kohno and Atsushi Baba and Katsuhiko Mikoshiba and Kazunori Nakajima and Mitsuharu Hattori",
year = "2007",
month = "7",
day = "13",
doi = "10.1074/jbc.M702300200",
language = "English",
volume = "282",
pages = "20544--20552",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "28",

}

TY - JOUR

T1 - The extremely conserved C-terminal region of Reelin is not necessary for secretion but is required for efficient activation of downstream signaling

AU - Nakano, Yoshimi

AU - Kohno, Takao

AU - Hibi, Terumasa

AU - Kohno, Shiori

AU - Baba, Atsushi

AU - Mikoshiba, Katsuhiko

AU - Nakajima, Kazunori

AU - Hattori, Mitsuharu

PY - 2007/7/13

Y1 - 2007/7/13

N2 - Reelin is a very large secreted glycoprotein essential for correct development of the mammalian brain. It is also implicated in higher functions and diseases of human brain. However, whether or not secretion of Reelin is regulated and how Reelin transmits signals remain largely unknown. Reelin protein is composed of an N-terminal F-spondin-like domain, Reelin repeats, and a short and highly basic C-terminal region (CTR). The primary sequence of CTR is almost completely conserved among vertebrates except fishes, indicating its importance. A prevailing idea regarding the function of CTR is that it is required for the secretion of Reelin, although this remains unproven. Here we aimed to clarify the function of Reelin CTR. Neither deleting most of CTR nor replacing CTR with unrelated amino acids affected secretion efficiency, indicating that CTR is not absolutely required for the secretion of Reelin. We also found that Reelin mutants without CTR were less potent in activating the downstream signaling in cortical neurons. Although these mutants were able to bind to the Reelin receptor ectodomain as efficiently as wild-type Reelin, quite interestingly, their ability to bind to the isolated cell membrane bearing Reelin receptors or receptor-expressing cells (including cortical neurons) was much weaker than that of wild-type Reelin. Therefore, it is concluded that the CTR of Reelin is not essential for its secretion but is required for efficient activation of downstream signaling events, presumably via binding to an unidentified "coreceptor" molecule(s) on the cell membrane.

AB - Reelin is a very large secreted glycoprotein essential for correct development of the mammalian brain. It is also implicated in higher functions and diseases of human brain. However, whether or not secretion of Reelin is regulated and how Reelin transmits signals remain largely unknown. Reelin protein is composed of an N-terminal F-spondin-like domain, Reelin repeats, and a short and highly basic C-terminal region (CTR). The primary sequence of CTR is almost completely conserved among vertebrates except fishes, indicating its importance. A prevailing idea regarding the function of CTR is that it is required for the secretion of Reelin, although this remains unproven. Here we aimed to clarify the function of Reelin CTR. Neither deleting most of CTR nor replacing CTR with unrelated amino acids affected secretion efficiency, indicating that CTR is not absolutely required for the secretion of Reelin. We also found that Reelin mutants without CTR were less potent in activating the downstream signaling in cortical neurons. Although these mutants were able to bind to the Reelin receptor ectodomain as efficiently as wild-type Reelin, quite interestingly, their ability to bind to the isolated cell membrane bearing Reelin receptors or receptor-expressing cells (including cortical neurons) was much weaker than that of wild-type Reelin. Therefore, it is concluded that the CTR of Reelin is not essential for its secretion but is required for efficient activation of downstream signaling events, presumably via binding to an unidentified "coreceptor" molecule(s) on the cell membrane.

UR - http://www.scopus.com/inward/record.url?scp=34547115035&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34547115035&partnerID=8YFLogxK

U2 - 10.1074/jbc.M702300200

DO - 10.1074/jbc.M702300200

M3 - Article

C2 - 17504759

AN - SCOPUS:34547115035

VL - 282

SP - 20544

EP - 20552

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 28

ER -