IKK1 vs IKK2?

IKK1 podria ser antagonista de la activacion de NFkB. Esto coincide con papers previos en los que los niveles relativos de IKK1 y 2 determinaban la activacion de NFkB y un articulo previo de IKK1 como inhibidor en macrofagos. En el caso del TIMP seria interesante analizar los niveles de ambas.

Zebrafish IκB Kinase 1 Negatively Regulates NF-κB Activity Ricardo G. Correa, Takaaki Matsui Vinay Tergaonkar, Concepcion Rodriguez-Esteban, Juan Carlos Izpisua-Belmonte and Inder M. Verma. Curr. Biol. 15: 26 July 2005, Pages 1291-1295
The IκB kinase (IKK) activity is critical for processing IκB inhibitory proteins and activating the NF-κB signaling, which is involved in a series of physiological and developmental steps in vertebrates [1, 2, 3 and 4]. The IKK activity resides in two catalytic subunits, IKK1 and IKK2, and two regulatory subunits, NEMO and ELKS [5, 6, 7 and 8]. IKK2 is the major cytokine-responsive IκB kinase [9, 10 and 11] because depletion of IKK1 does not interfere with the IKK activity [12, 13 and 14]. In fact, IKK1^−/− mice display morphological abnormalities that are independent of its kinase activity and NF-κB activation [12, 13 and 14]. Hence, using zebrafish (Danio rerio) as a model, we examined the evolutionary role of IKK1 in modulating NF-κB. Ikk1^−/− zebrafish embryos present head and tail malformations and, surprisingly, show upregulation of NF-κB-responsive genes and increased NF-κB-dependent apoptosis. Overexpression of ikk1 leads to midline structure defects that resemble NF-κB blockage in vivo [1]. Zebrafish Ikk1 forms complexes with NEMO that represses NF-κB in vertebrate cells. Indeed, truncation of its NEMO binding domain (NBD) restores NF-κB-dependent transcriptional activity and, consequently, the ikk1-overexpressing phenotype. Here, we report that Ikk1 negatively regulates NF-κB by sequestering NEMO from active IKK complexes, indicating that IKK1 can function as a repressor of NF-κB.

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