Washington University

Andrey S Shaw

Anthony J Muslin

Gabriel Waksman

Jiancheng Hu

Haiyang Yu

Mutant KSR proteins are disclosed. The mutants include single amino acid substitutions, leading to either a loss of kinase activity or a loss of scaffolding activity. Also disclosed are methods of screening compounds for inhibitors of KSR kinase activity or KSR scaffolding activity. In some embodiments, the screening methods include protein complementation assays in which nucleic acids encoding fusion constructs comprising enzyme portions and kinase dimerization domains are expressed in cells. Inhibitors of dimerization can be indicated by loss of enzyme activity.

Methods and uses of KSR kinase, and mutations thereof

Compositions and methods for inhibition of the intracellular activation of a signal transducing protein comprising phosphoserine containing peptides derived from the Raf-1 protein are disclosed. The peptides bind to 14-3-3 protein and thereby prevent its association with the signal transducing peptide to block signal transduction. Also provided is an assay method for identifying a pharmacologic agent that can bind 14-3-3 protein and block signal transduction.

Inhibition of intracellular signal transduction by 14-3-3-binding peptides

Inhibition of intracellular signal transduction by 14-3-3-binding

Modified SH2 domains of intracellular proteins and methods of use, wherein the SH2 domains are modified to include an altered binding site for a signal transduction protein. The binding site is altered to either change the specificity of the SH2 domain for a signal transduction protein that is not the natural ligand or to include a reactive group, such as a reactive amino acid, that reacts with a phosphorylated amino acid of the signal transduction protein. The modified SH2 domains are useful as research tools or in methods for inactivating or inhibiting signal transduction proteins, especially those that contribute to disease or disorders such as cancer or for targeting specific SH2 domains for diagnostics.

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St. Louis, MO, United States of America

Andrey S Shaw