Cellular signaling gene transcription

Phosphorylation is the reversible process of introducing a phosphate group onto a protein. Phosphorylation occurs on the hydroxyamino acids serine and threonine or on tyrosine residues targeted by Ser/Thr kinases and tyrosine kinases respectively. Dephosphorylation is catalyzed by phosphatases. Phosphorylation is a key mechanism for rapid posttranslational modulation of protein function. It is widely exploited in cellular processes to control various aspects of cell signaling, cell proliferation, cell differentiation, cell survival, cell metabolism, cell motility, and gene transcription. 

Proteasomal degradation also plays an essential role in the activation of cellular signaling pathways. A prototype for this is the control of NF-kB signaling, which has a pivotal role in inflammatory responses. Upon stimulation the inhibitory IicBa protein is phos-phorylated and thereby becomes a target substrate for K48-polyubiquitination. Proteasomal degradation of IkBu releases the transcription factor NF-kB, which subsequently translocates to the nucleus and activates specific target genes. 

Some members of this family have been shown to mediate the dephosphorylation of MAPKs under physiological conditions. Others dephosphorylate Cdc-2 and related CDKs. However, relatively little is known to date about the regional distribution of these dual-functioning phosphatases in the brain and the specific function these enzymes serve in the regulation of neuronal signal transduction. Considerable interest has focused on one particular MAPK phosphatase, which can be induced very rapidly, at the level of gene transcription, in target cells in response to cellular activation [44]. 

As was mentioned earlier, DAG activates protein kinase C, which phosphorylates transcription factors like NFjcB nuclear transcription factor. NFjcB forms a multisubunit complex with an inhibitory subunit which is phosphorylated by PKC. The complex disintegrates and what is released translocates to the nucleus and initiates gene transcription. NFjcB is a heterodimer, with two distinct DNA-binding subunits 50 kDa and 65 kDa, both being members of the Rel transcription factor family. These proteins have an important role in the signaling cascade of the cellular defense system, and activate numerous genes in response to pathogens or inflammatory cytokines. 

The downstream effectors of TRAF signaling are transcription factors in the nuclear factor k-B (NF-kB) and activator protein-1 (AP-1) family (Ghosh and Karin, 2002 Shaulian and Karin, 2002), which can turn on numerous genes involved in many aspects of cellular and immune functions. While the carboxyl terminal TRAF domain, containing a coiled-coil TRAF-N domain and a conserved TRAF-C domain, is both necessary and sufficient for TRAF self-association and receptor interaction, the amino terminal domain, containing RING and zinc-finger motifs, is important for downstream functions (Rothe et al, 1994). 

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