FLICE, A Novel FADD-Homologous ICE/CED-3–like Protease, Is Recruited to the CD95 (Fas/APO-1) Death-Inducing Signaling Complex

These results strongly suggest that CAP3 and CAP4 are downstream components of the CD95 signaling cascade

Marta Muzio; Arul M Chinnaiyan; Frank C Kischkel; Karen O'Rourke; Andrej Shevchenko; Jian Ni; Carsten Scaffidi; James D Bretz; Mei Zhang; Reiner Gentz; Matthias Mann; Peter H Krammer; Marcus E Peter; Vishva M Dixit

2004

Scholarcy highlights

  • Apoptosis, or programmed cell death, is a genetically regulated mechanism with a central role in both metazoan development and homeostasis
  • Subsequent dominant-negative studies have established that endogenous Fasassociating protein with death domain is essential for the recruitment of CAP3 and CAP4 to the CD95 deathinducing signaling complex
  • When the Human Genome Sciences cDNA database was searched, a 3.0 kb cDNA was identified and found to contain a 1437 bp open reading frame that encoded a novel protein with a predicted molecular mass of 55.3 kDa and a pI of 4.91, consistent with the size and pI of CAP4, as determined by 2D gel analysis
  • A BLAST search of the GenBank protein database revealed that the novel cDNA, designated FLICE, had substantial homology to both FADD and the interleukin-1␤–converting enzyme/CED-3 family of cysteine proteases
  • The CD95-mediated apoptotic cascade is initiated by the direct physical association of the death receptor CD95 with the adaptor molecule FADD and the effector protease FLICE, a novel member of the ICE/CED-3 family
  • The death domain of the receptor binds to the death domain of the adaptor molecule FADD, which, in a manner that remains to be determined, binds and activates FLICE to generate the most apical enzymatic component of a death cascade composed of other ICE/CED-3 family members
  • The mode of assembly of the deathinducing signaling complex and the mechanism by which FLICE is activated will be critical questions for future investigation

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