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Biotech / Medical : T/FIF, a New Plateau -- Ignore unavailable to you. Want to Upgrade?

To: tuck who wrote (822)	1/23/2002 10:46:05 PM
From: scaram(o)uche	Read Replies (1) \| Respond to of 2243

"Error: One of the required fields in the search form was not filled in. Details: USDI, SPN, or USERNAME cookie is missing."

To: tuck who wrote (822)	1/25/2002 8:58:24 PM
From: scaram(o)uche	Read Replies (1) \| Respond to of 2243

They've been working with a ubiquitin ligase that is thought to ubiquinate both HER-2 and EGFR. Sorry, but I'm confused/missing something important, as it seems to me that you would want to enhance the ubiquitination? Truncated forms of the receptors?..... gotta see some preclinical data....... the prospectus supplement that was described in the "Robby Stephens offering" PR doesn't have anything??...... J Exp Med 2001 Nov 5;194(9):1263-76 Functional cloning of Src-like adapter protein-2 (SLAP-2), a novel inhibitor of antigen receptor signaling. Holland SJ, Liao XC, Mendenhall MK, Zhou X, Pardo J, Chu P, Spencer C, Fu A, Sheng N, Yu P, Pali E, Nagin A, Shen M, Yu S, Chan E, Wu X, Li C, Woisetschlager M, Aversa G, Kolbinger F, Bennett MK, Molineaux S, Luo Y, Payan DG, Mancebo HS, Wu J. Rigel, Incorporated, South San Francisco, CA 94080, USA. In an effort to identify novel therapeutic targets for autoimmunity and transplant rejection, we developed and performed a large-scale retroviral-based functional screen to select for proteins that inhibit antigen receptor-mediated activation of lymphocytes. In addition to known regulators of antigen receptor signaling, we identified a novel adaptor protein, SLAP-2 which shares 36% sequence similarity with the known Src-like adaptor protein, SLAP. Similar to SLAP, SLAP-2 is predominantly expressed in hematopoietic cells. Overexpression of SLAP-2 in B and T cell lines specifically impaired antigen receptor-mediated signaling events, including CD69 surface marker upregulation, nuclear factor of activated T cells (NFAT) promoter activation and calcium influx. Signaling induced by phorbol myristate acetate (PMA) and ionomycin was not significantly reduced, suggesting SLAP-2 functions proximally in the antigen receptor signaling cascade. The SLAP-2 protein contains an NH2-terminal myristoylation consensus sequence and SH3 and SH2 Src homology domains, but lacks a tyrosine kinase domain. In antigen receptor-stimulated cells, SLAP-2 associated with several tyrosine phosphorylated proteins, including the ubiquitin ligase Cbl. Deletion of the COOH terminus of SLAP-2 blocked function and abrogated its association with Cbl. Mutation of the putative myristoylation site of SLAP-2 compromised its inhibitory activity and impaired its localization to the membrane compartment. Our identification of the negative regulator SLAP-2 demonstrates that a retroviral-based screening strategy may be an efficient way to identify and characterize the function of key components of many signal transduction systems. ******************* Could be one of many ligases that they've worked with????