Impaired binding of 14-3-3 to C-RAF in noonan syndrome suggests new approaches in diseases with increased ras signaling

The Ras-RAF-mitogen-activated protein kinase (Ras-RAF-MAPK) pathway is overactive in many cancers and in some developmental disorders. In one of those disorders, namely, Noonan syndrome, nine activating C-RAF mutations cluster around Ser(259), a regulatory site for inhibition by 14-3-3 proteins. We show that these mutations impair binding of 14-3-3 proteins to C-RAF and alter its subcellular localization by promoting Ras-mediated plasma membrane recruitment of C-RAF. By presenting biophysical binding data, the 14-3-3/C-RAFpS(259) crystal structure, and cellular analyses, we indicate a mechanistic link between a well-described human developmental disorder and the impairment of a 14-3-3/target protein interaction. As a broader implication of these findings, modulating the C-RAFSer(259)/14-3-3 protein-protein interaction with a stabilizing small molecule may yield a novel potential approach for treatment of diseases resulting from an overactive Ras-RAF-MAPK pathway

Invariant Definability and P/poly

. We look at various uniform and non-uniform complexity classes within P=poly and its variations L=poly, NL=poly, NP=poly and PSpace=poly, and look for analogues of the Ajtai-Immerman theorem which characterizes AC0 as the non-uniformly First Order Definable classes of finite structures. We have previously observed that the AjtaiImmerman theorem can be rephrased in terms of invariant definability: A class of finite structures is FOL invariantly definable iff it is in AC0 . Invariant definability is a notion closely related to but different from implicit definability and \Delta-definability. Its exact relationship to these other notions of definability has been determined in [Mak97]. Our first results are a slight generalization of similar results due to Molzan and can be stated as follows: let C be one of L; NL;P, NP, PSpace and L be a logic which captures C on ordered structures. Then the non-uniform L-invariantly definable classes of (not necessarily ordered) finite structures are..

The Turing Machine Paradigm in Contemporary Computing

this paper we will extend the Turing machine paradigm to include several key features of contemporary information processing systems