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Vol. 19, Issue 8, 3192-3202, August 2008

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A Novel Juxtamembrane Domain in Tumor Necrosis Factor Receptor Superfamily Molecules Activates Rac1 and Controls Neurite Growth

Department of Physiology, McGill University, Montréal, Québec H3G 1Y6, Canada

Submitted February 15, 2008; Revised April 29, 2008; Accepted May 19, 2008
Monitoring Editor: Kunxin Luo

Members of the tumor necrosis factor receptor (TNFR) superfamily control cell fate determination, including cell death and differentiation. Fas (CD95) is the prototypical "death receptor" of the TNFR superfamily and signals apoptosis through well established pathways. In the adult nervous system, Fas induces apoptosis in the context of neuropathology such as stroke or amyotrophic lateral sclerosis. However, during nervous system development, Fas promotes neurite growth and branching. The molecular mechanisms underlying Fas-induced process formation and branching have remained unknown to date. Here, we define the molecular pathway linking Fas to process growth and branching in cell lines and in developing neurons. We describe a new cytoplasmic membrane proximal domain (MPD) that is essential for Fas-induced process growth and that is conserved in members of the TNFR superfamily. We show that the Fas MPD recruits ezrin, a molecule that links transmembrane proteins to the cytoskeleton, and activates the small GTPase Rac1. Deletion of the MPD, but not the death domain, abolished Rac1 activation and process growth. Furthermore, an ezrin-derived inhibitory peptide prevented Fas-induced neurite growth in primary neurons. Our results define a new domain, topologically and functionally distinct from the death domain, which regulates neuritogenesis via recruitment of ezrin and activation of Rac1.

* Present address: Tosteson Medical Education Center, Harvard Medical School, Boston, MA 02115.

Address correspondence to: Julie Desbarats (julie.desbarats{at}mcgill.ca)

Abbreviations used: CRIB, Cdc42/Rac1-interactive binding; DD, death domain; ERK, p42/44 extracellular signal-regulated kinase; FADD, Fas-associated death domain; FasL, Fas ligand; ICD, intracellular domain; luc, luciferase; MPD, membrane proximal domain; NGFR, low-affinity p75 nerve growth factor receptor; PAK1B, p21-activated kinase 1 protein 1B; RBD, Rho binding domain; ROCK, Rho-associated kinase; TNFR, tumor necrosis factor receptor.