Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway

Isamu Okamoto, Yoshiaki Kawano, Daizo Murakami, Takashi Sasayama, Norie Araki, Toru Miki, Albert J. Wong, Hideyuki Saya

Research output: Contribution to journalArticle

271 Citations (Scopus)

Abstract

CD44 is a widely distributed cell surface adhesion molecule and is implicated in diverse biological processes. However, the nature of intracellular signaling triggered by CD44 remains to be elucidated. Here, we show that CD44 undergoes sequential proteolytic cleavage in the ectodomain and intracellular domain, resulting in the release of a CD44 intracellular domain (ICD) fragment. Consequently, CD44ICD acts as a signal transduction molecule, where it translocates to the nucleus and activates transcription mediated through the 12-O-tetradecanoylphorbol 13-acetate-responsive element, which is found in numerous genes involved in diverse cellular processes. Expression of an uncleavable CD44 mutant as well as metalloprotease inhibitor treatment blocks CD44-mediated transcriptional activation. In search of the underlying mechanism, we have found that CD44ICD potentiates transactivation mediated by the transcriptional coactivator CBP/p300. Furthermore, we show that cells expressing CD44ICD produce high levels of CD44 messenger RNA, suggesting that the CD44 gene is one of the potential targets for transcriptional activation by CD44ICD. These observations establish a novel CD44 signaling pathway and shed new light on the functional link between proteolytic processing of an adhesion molecule at the cell surface and transcriptional activation in the nucleus.

Original languageEnglish
Pages (from-to)755-762
Number of pages8
JournalJournal of Cell Biology
Volume155
Issue number5
DOIs
Publication statusPublished - Nov 26 2001

Fingerprint

Transcriptional Activation
Cell Adhesion Molecules
p300-CBP Transcription Factors
Biological Phenomena
Metalloproteases
Tetradecanoylphorbol Acetate
Genes
Signal Transduction
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway. / Okamoto, Isamu; Kawano, Yoshiaki; Murakami, Daizo; Sasayama, Takashi; Araki, Norie; Miki, Toru; Wong, Albert J.; Saya, Hideyuki.

In: Journal of Cell Biology, Vol. 155, No. 5, 26.11.2001, p. 755-762.

Research output: Contribution to journalArticle

Okamoto, I, Kawano, Y, Murakami, D, Sasayama, T, Araki, N, Miki, T, Wong, AJ & Saya, H 2001, 'Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway', Journal of Cell Biology, vol. 155, no. 5, pp. 755-762. https://doi.org/10.1083/jcb.200108159
Okamoto, Isamu ; Kawano, Yoshiaki ; Murakami, Daizo ; Sasayama, Takashi ; Araki, Norie ; Miki, Toru ; Wong, Albert J. ; Saya, Hideyuki. / Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway. In: Journal of Cell Biology. 2001 ; Vol. 155, No. 5. pp. 755-762.
@article{a813fc7fe7f24e22b96cc01825d528a8,
title = "Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway",
abstract = "CD44 is a widely distributed cell surface adhesion molecule and is implicated in diverse biological processes. However, the nature of intracellular signaling triggered by CD44 remains to be elucidated. Here, we show that CD44 undergoes sequential proteolytic cleavage in the ectodomain and intracellular domain, resulting in the release of a CD44 intracellular domain (ICD) fragment. Consequently, CD44ICD acts as a signal transduction molecule, where it translocates to the nucleus and activates transcription mediated through the 12-O-tetradecanoylphorbol 13-acetate-responsive element, which is found in numerous genes involved in diverse cellular processes. Expression of an uncleavable CD44 mutant as well as metalloprotease inhibitor treatment blocks CD44-mediated transcriptional activation. In search of the underlying mechanism, we have found that CD44ICD potentiates transactivation mediated by the transcriptional coactivator CBP/p300. Furthermore, we show that cells expressing CD44ICD produce high levels of CD44 messenger RNA, suggesting that the CD44 gene is one of the potential targets for transcriptional activation by CD44ICD. These observations establish a novel CD44 signaling pathway and shed new light on the functional link between proteolytic processing of an adhesion molecule at the cell surface and transcriptional activation in the nucleus.",
author = "Isamu Okamoto and Yoshiaki Kawano and Daizo Murakami and Takashi Sasayama and Norie Araki and Toru Miki and Wong, {Albert J.} and Hideyuki Saya",
year = "2001",
month = "11",
day = "26",
doi = "10.1083/jcb.200108159",
language = "English",
volume = "155",
pages = "755--762",
journal = "Journal of Cell Biology",
issn = "0021-9525",
publisher = "Rockefeller University Press",
number = "5",

}

TY - JOUR

T1 - Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway

AU - Okamoto, Isamu

AU - Kawano, Yoshiaki

AU - Murakami, Daizo

AU - Sasayama, Takashi

AU - Araki, Norie

AU - Miki, Toru

AU - Wong, Albert J.

AU - Saya, Hideyuki

PY - 2001/11/26

Y1 - 2001/11/26

N2 - CD44 is a widely distributed cell surface adhesion molecule and is implicated in diverse biological processes. However, the nature of intracellular signaling triggered by CD44 remains to be elucidated. Here, we show that CD44 undergoes sequential proteolytic cleavage in the ectodomain and intracellular domain, resulting in the release of a CD44 intracellular domain (ICD) fragment. Consequently, CD44ICD acts as a signal transduction molecule, where it translocates to the nucleus and activates transcription mediated through the 12-O-tetradecanoylphorbol 13-acetate-responsive element, which is found in numerous genes involved in diverse cellular processes. Expression of an uncleavable CD44 mutant as well as metalloprotease inhibitor treatment blocks CD44-mediated transcriptional activation. In search of the underlying mechanism, we have found that CD44ICD potentiates transactivation mediated by the transcriptional coactivator CBP/p300. Furthermore, we show that cells expressing CD44ICD produce high levels of CD44 messenger RNA, suggesting that the CD44 gene is one of the potential targets for transcriptional activation by CD44ICD. These observations establish a novel CD44 signaling pathway and shed new light on the functional link between proteolytic processing of an adhesion molecule at the cell surface and transcriptional activation in the nucleus.

AB - CD44 is a widely distributed cell surface adhesion molecule and is implicated in diverse biological processes. However, the nature of intracellular signaling triggered by CD44 remains to be elucidated. Here, we show that CD44 undergoes sequential proteolytic cleavage in the ectodomain and intracellular domain, resulting in the release of a CD44 intracellular domain (ICD) fragment. Consequently, CD44ICD acts as a signal transduction molecule, where it translocates to the nucleus and activates transcription mediated through the 12-O-tetradecanoylphorbol 13-acetate-responsive element, which is found in numerous genes involved in diverse cellular processes. Expression of an uncleavable CD44 mutant as well as metalloprotease inhibitor treatment blocks CD44-mediated transcriptional activation. In search of the underlying mechanism, we have found that CD44ICD potentiates transactivation mediated by the transcriptional coactivator CBP/p300. Furthermore, we show that cells expressing CD44ICD produce high levels of CD44 messenger RNA, suggesting that the CD44 gene is one of the potential targets for transcriptional activation by CD44ICD. These observations establish a novel CD44 signaling pathway and shed new light on the functional link between proteolytic processing of an adhesion molecule at the cell surface and transcriptional activation in the nucleus.

UR - http://www.scopus.com/inward/record.url?scp=0035956428&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035956428&partnerID=8YFLogxK

U2 - 10.1083/jcb.200108159

DO - 10.1083/jcb.200108159

M3 - Article

C2 - 11714729

AN - SCOPUS:0035956428

VL - 155

SP - 755

EP - 762

JO - Journal of Cell Biology

JF - Journal of Cell Biology

SN - 0021-9525

IS - 5

ER -