Cellular kinase complex

NF-kB comprises a family of inducible transcription factors that serve as relevant mediators of the inflammatory response. This factor is also involved in protecting cells from undergoing apoptosis in response to DNA damage or treatment with cytokine [89]. Normally, NF-kB is kept inactive by a cytoplasmic inhibitor of kB (IkB) proteins, which are phosphorylated by a cellular kinase complex known as IKK, made up of two kinases, IKK-a and IKK-p. The phosphorylation of IkB by these kinases leads to the degradation of the proteins and to the translocation of NF-kB to the nucleus. Once in the nucleus, NF-kB activates gene expression of cells exposed to growth factors and cytokines [90,91]. Activation of the NF-kB pathway is thus involved in the pathogenesis of chronic inflammatory diseases such as rheumatoid arthritis and asthma... 

The CSN3 subunit interacts with IKKy, a component of the IsrB-kinase complex controlling NF-kB activity [32]. Additionally, it is the binding site for the CSN-associated kinases CK2 and PKD [31]. The subunit of the translation-initiation factor 3 complex, Int6/eIF3e, and the ubiquitin-conjugating enzyme variant, COPIO, have been identified as other cellular interactors [33, 34]. Also the HIV-1 Tat protein interacts with CSN 3 (our unpublished data). 

As well as its effect on the translation of inhibitory potency against the intended target to cellular activity, the complex whole-cell situation can have a profound effect on the observed selectivity of kinase inhibitors. A small selection of data for the type II inhibitor sorafenib 8 demonstrates the potential for selectivity profiles to be different when comparing isolated enzyme or whole cell data, showing it to be a more potent inhibitor of Flt-3 relative to VEGFR-2, PDGFR-p and c-Kit in cells than would be predicted from its kinase inhibitory profile (Table 3.2).23 Probing the mechanistic basis for cellular kinase inhibitor selectivity, researchers at the University of California demonstrated that differential pathway sensitivity could lead to selective effects in cells.24... 

Phosphorylation by protein kinases of specific seryl, threonyl, or tyrosyl residues—and subsequent dephosphorylation by protein phosphatases—regulates the activity of many human enzymes. The protein kinases and phosphatases that participate in regulatory cascades which respond to hormonal or second messenger signals constimte a bio-organic computer that can process and integrate complex environmental information to produce an appropriate and comprehensive cellular response. 

The very beginning of the first mitotic cell cycle of the mouse embryo seems to be controlled by the mechanisms characteristic for both meiotic and mitotic cell cycles. Active MAP kinase, its substrate p90rsk and the CSF activity itself could influence the cellular processes within the one-cell embryo. Indeed, we have observed that despite the entry into the interphase (as judged by the low activity of MPF) some proteins are actively phosphorylated as during the meiotic M phase (e.g. 35 kDa complex Howlett et al 1986, Szollosi et al 1993), the nuclei and the microtubule interphase network start to form only 1.5 hours after activation (Szollosi et al 1993). This delay in the phenomena characteristic for the interphase could be linked to the mixed meiotic/mitotic character of this early period. This delay probably allows the correct transformation of the sperm nucleus into the male pronucleus. In species like Xenopus or Drosophila the transitional period between the meiotic and the mitotic cell cycle control is probably much shorter since it is proportional to duration of the short first cell cycle of these rapidly cleaving embryos. Mammalian embryos are perhaps the most suitable to study this transition because of the exceptionally long first embryonic cell cycle. 

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