HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 36, 31360-31367, September 9, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/36/31360    most recent M504138200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Imtiyaz, H. Z. Articles by Zhang, J. Search for Related Content PubMed PubMed Citation Articles by Imtiyaz, H. Z. Articles by Zhang, J. Social Bookmarking                      What's this?

Structural Requirements for Signal-induced Target Binding of FADD Determined by Functional Reconstitution of FADD Deficiency^*

Hongxia Z. Imtiyaz, Yuhang Zhang, and Jianke Zhang

From the Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

FADD is a key adaptor modulating several signaling pathways such as apoptosis induced by Fas (CD95) and tumor necrosis factor receptor 1, and cell proliferation induced by mitogens. Whereas mutations in Fas disrupt its binding to FADD and cause autoimmune lymphoproliferative (lpr) syndromes, a FADD deficiency blocks embryonic development in mice. To delineate the multifunction of FADD in vivo, we performed functional reconstitution analysis by introducing wild type and mutant FADD into FADD^–/– cells or FADD^–/– mice lacking the endogenous FADD. An lpr-like FADD mutant, V121N, was reported previously as being defective in Fas binding in vitro. However, we found that in mice V121N can bind to Fas and is functional in signaling apoptosis. Unexpectedly, this lpr-like mutant FADD failed to support mouse development, indicating that the death domain of FADD has an additional function required for embryogenesis, which is independent of that required for receptor-induced apoptosis. Further mutagenesis was targeted at charged residues in the FADD death domain, presumably mediating electrostatic interactions with Fas. We showed that the target binding and apoptosis signaling functions of FADD were not affected when mutations were introduced to a majority of the charged residues. In one exception, replacing arginine 117 with an uncharged residue disrupted target binding and apoptosis signaling, but restoring the positive charge at position 117 failed to reconstitute the FADD function. Therefore, in vivo target binding of FADD involves an additional mechanism distinct from electrostatic interaction.

Received for publication, April 15, 2005 , and in revised form, June 14, 2005.

^* This work was supported by Grant RO1 CA95454 from the NCI, National Institutes of Health, and grants from the W. W. Smith Charitable Trust and CONCERN Foundation (to J. Z.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Kimmel Cancer Center and Dept. of Microbiology and Immunology, Thomas Jefferson University, 233 S. 10th St., Rm. 731 BLSB, Philadelphia, PA 19107. Tel.: 215-503-4559; Fax: 215-923-4153; E-mail: jzhang{at}mail.jci.tju.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				H. Z. Imtiyaz, S. Rosenberg, Y. Zhang, Z. S. M. Rahman, Y.-J. Hou, T. Manser, and J. Zhang The Fas-Associated Death Domain Protein Is Required in Apoptosis and TLR-Induced Proliferative Responses in B Cells. J. Immunol., June 1, 2006; 176(11): 6852 - 6861. [Abstract] [Full Text] [PDF]