Signaling
The downstream target of Elk1 is the serum response element (SRE) of the c-fos proto-oncogene. To produce c-fos, a protein encoded by the Fos gene, Elk1 needs to be phosphorylated by MAPKs at its C-terminus. MAPKs are the final effectors of signal transduction pathways that begin at the plasma membrane. Phosphorylation by MAPKs results in a conformational change of Elk1. As seen in Figure 2, Raf kinase acts upstream of MAPKs to activate them by phosphorylating and, thereby activating, MEKs, or MAPK or ERK kinases. Raf itself is activated by Ras, which is linked to growth factor receptors with tyrosine kinase activity via Grb2 and Sos. Grb2 and Sos can stimulate Ras only after the binding of growth factors to their corresponding receptors. However, Raf activation does not exclusively depend on Ras. Protein kinase C, which is activated by phorbol esters, can fulfill the same function as Ras. MEK kinase (MEKK) can also activate MEKs, which then activate MAPKs, making Raf unnecessary at times. Various signal transduction pathways, therefore, funnel through MEKs and MAPKs and lead to the activation of Elk1. After stimulation of Elk1, SRF, which allows Elk1 to bind to the c-fos promoter, must be recruited. The binding of Elk1 to SRF happens due to protein-protein interaction between the B domain of Elk1 and SRF and the protein-DNA interaction via the A domain.
The aforementioned proteins are like recipes for a certain signaling output. If one of these ingredients, such as SRF, is missing, then a different output occurs. In this case, lack of SRF leads to Elk1’s activation of another gene. Elk1 can, thus, independently interact with an ETS binding site, as in the case of the lck proto-oncogene in Figure 2. Moreover, the spacing and relative orientation of the Elk1 binding site to the SRE is rather flexible, suggesting that the SRE-regulated early genes other than c-fos could be targets of Elk1. egr-1 is an example of an Elk1 target that depends on SRE interaction. Ultimately, phosphorylation of Elk1 can result in the production of many proteins, depending on the other factors involved and their specific interactions with each other.
When studying signaling pathways, mutations can further highlight the importance of each component used to activate the downstream target. For instance, disruption of the C-terminal domain of Elk1 that MAPK phosphorylates triggers inhibition of c-fos activation. Similarly, dysfunctional SRF, which normally tethers Elk1 to the SRE, leads to Fos not being transcribed. At the same time, without Elk1, SRF cannot induce c-fos transcription after MAPK stimulation. For these reasons, Elk1 represents an essential link between signal transduction pathways and the initiation of gene transcription.
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