C - Chemistry – Metallurgy – 07 – K
Patent
C - Chemistry, Metallurgy
07
K
C07K 14/47 (2006.01) C12N 15/11 (2006.01) G01N 33/68 (2006.01)
Patent
CA 2604580
This invention demonstrates that KRC molecules have multiple important functions as modulating agents in regulating a wide variety of cellular processes including bone formation and mineralization. TGF-.beta. signaling in osteoblasts promotes the formation of a multimeric complex between KRC, Runx2, Smad3, and the E3 ubiquitin ligase, WWPl which inhibits Runx2 function due to the ability of WWPl to promote Runx2 polyubiquitination and proteasome- dependent degradation. Furthermore, KRC and WWPl form a complex with RSK2 which promotes RSK2 phosphorylation and inhibits RSK2 function due to the ability of WWP 1 to promote RSK2 ubiquitination. Methods for identifying modulators of KRC activity are provided. Methods for modulating an immune response, bone formation and mineralization, and KRC-associated disorders using agents that modulate KRC expression and/or activity are also provided.
L'invention porte sur la démonstration selon laquelle les molécules KRC possèdent de multiples fonctions importantes en tant qu'agents modulateurs, pour la régulation d'un large éventail de processus cellulaires, notamment la formation et la minéralisation osseuses. La signalisation du TGF-ß dans les ostéoblastes, active. la formation d'un complexe multimère entre KRC, Runx2, Smad3, et la ligase de l'ubiquitine E3, WWPl qui bloque la fonction de Runx2 en raison de la capacité de WWPl d'activer la polyubiquitination de Runx2 et la dégradation protéasomique. En outre KRC et WWPl forment un complexe avec RSK2 qui active la phosphorylation de RSK2 et bloque la fonction de RSK2 en raison de la capacité de WWP 1 d'activer l'ubiquitination de RSK2. L'invention concerne en outre des procédés permettant d'identifier des modulateurs de l'activité de KRC. L'invention concerne également des méthodes de modulation de la réponse immunitaire, et de la formation et de la minéralisation osseuse, et des troubles liés à KRC, par l'utilisation d'agent modulant l'expression est/ou l'activité de KRC.
Glimcher Laurie H. M.d.
Jones Dallas C.
Wein Marc
Borden Ladner Gervais Llp
President And Fellows Of Harvard College
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