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Biotech / Medical : Rigel Pharmaceuticals, Inc. (RIGL) -- Ignore unavailable to you. Want to Upgrade?

To: tuck who wrote (204)	6/13/2004 11:25:31 PM
From: keokalani'nui	Read Replies (1) \| Respond to of 566

J Immunol. 2004 Jun 15;172(12):7324-34. Related Articles, Links A Novel Role for p21-Activated Protein Kinase 2 in T Cell Activation. Chu PC, Wu J, Liao XC, Pardo J, Zhao H, Li C, Mendenhall MK, Pali E, Shen M, Yu S, Taylor VC, Aversa G, Molineaux S, Payan DG, Masuda ES. Rigel, Inc., South San Francisco, CA 94080; and. To identify novel components of the TCR signaling pathway, a large-scale retroviral-based functional screen was performed using CD69 expression as a marker for T cell activation. In addition to known regulators, two truncated forms of p21-activated kinase 2 (PAK2), PAK2DeltaL(1-224) and PAK2DeltaS(1-113), both lacking the kinase domain, were isolated in the T cell screen. The PAK2 truncation, PAK2DeltaL, blocked Ag receptor-induced NFAT activation and TCR-mediated calcium flux in Jurkat T cells. However, it had minimal effect on PMA/ionomycin-induced CD69 up-regulation in Jurkat cells, on anti-IgM-mediated CD69 up-regulation in B cells, or on the migratory responses of resting T cells to chemoattractants. We show that PAK2 kinase activity is increased in response to TCR stimulation. Furthermore, a full-length kinase-inactive form of PAK2 blocked both TCR-induced CD69 up-regulation and NFAT activity in Jurkat cells, demonstrating that kinase activity is required for PAK2 function downstream of the TCR. We also generated a GFP-fused PAK2 truncation lacking the Cdc42/Rac interactive binding region domain, GFP-PAK2(83-149). We show that this construct binds directly to the kinase domain of PAK2 and inhibits anti-TCR-stimulated T cell activation. Finally, we demonstrate that, in primary T cells, dominant-negative PAK2 prevented anti-CD3/CD28-induced IL-2 production, and TCR-induced CD40 ligand expression, both key functions of activated T cells. Taken together, these results suggest a novel role for PAK2 as a positive regulator of T cell activation.

To: tuck who wrote (204)	10/22/2004 11:30:59 AM
From: tuck	Read Replies (1) \| Respond to of 566

[Poxvirus p28 virulence factor Is An E3 Ubiquitin ligase] >>J Biol Chem. 2004 Oct 20 [Epub ahead of print] The poxvirus p28 virulence factor Is An E3 Ubiquitin ligase. Huang J, Huang Q, Zhou X, Shen MM, Yen A, Yu SX, Dong G, Qu K, Huang P, Anderson EM, Daniel-Issakani S, Buller RM, Payan DG, Lu HH. Department of Virology, Rigel Pharmaceuticals, Inc., South San Francisco, CA 94080. A majority of the orthopoxviruses, including the variola virus that causes the dreaded smallpox disease, encode a highly conserved 28 kD protein with a classic RING finger sequence motif (C3HC4) at their carboxyl-terminal domains. The RING domain of p28 has been shown to be a critical determinant of viral virulence for the ectromelia virus (mousepox virus) in a murine infection model [Senkevich, T. G., Koonin, E. V. & Buller, R. M. (1994) Virology 198, 118-28]. Here we demonstrate that the p28 proteins encoded by the ectromelia virus and the variola virus possess E3 ubiquitin ligase activity in biochemical assays as well as in cultured mammalian cells. Point mutations disrupting the RING finger domain of p28 completely abolish its E3 ligase activity. In addition, p28 functions cooperatively with Ubc4 and UbcH5c, the E2 conjugating enzymes involved in 26S proteasome degradation of protein targets. Moreover, p28 catalyzes the formation of Lys-63 linked polyubiquitin chains in the presence of Ubc13/Uev1A, a heterodimeric E2 conjugating enzyme, indicating that p28 may regulate the biological activity of its cognate viral and/or host cell target(s) by Lys-63 linked ubiquitin multimers. We thus conclude that the poxvirus p28 virulence factor is a new member of the RING finger E3 ubiquitin ligase family, and has a unique polyubiquitylation activity. We propose that the E3 ligase activity of the p28 virulence factor may be targeted for therapeutic intervention against infections by the variola virus and other poxviruses.<< Do they even have the money to pursue ubiquitin ligase stuff? Maybe they can get a NAIAD grant for an anti-variola program or something . . . [Do three Huangs make a right?] Cheers, Tuck