Integration of Multiple Pathways

In a living organism, cells are unlikely to be stimulated by a single growth factor or cytokine, but rather will respond to a plethora of signals at one time. Consequently, cells have to integrate diverse inputs to produce a coordinated outcome. Different pathways may converge on a single transcription factor or promoter to regulate gene expression (Tan and Kim 1999). An example of this occurs in Drosophila where both EGF and DPP (decapentaplegic) signalling induce the expression of a gene termed labial, but each one alone is insufficient to promote expression (Szuts et al. 1998). In addition to converging on single targets, separate pathways can intersect on complexes of transcription factors. The complex of serum-response factor (SRF) and ELK-1 allows integration of Rho-mediated (Marais et al. 1993) and ERK-mediated (Hill et al. 1995) signalling pathways. Different signalling pathways could also intersect on proteins. This has been observed for the oestrogen receptor, which requires both oestrogen binding and phosphorylation by MAPK for maximal activation (Kato et al. 1995).

As well as synergistic relationships, crosstalk among signalling pathways may culminate in inhibition. In this situation, the inhibiting pathway would abrogate the activating signal. A response would occur only in cells that have the activating pathway, but lack the inhibiting pathway. For example, transforming growth factor P (TGF-P) signals through SMAD1, phosphorylation of which by ERK inhibits nuclear translocation, and transcriptional activity (Kretzschmar et al. 1997). Therefore, activation of the MEK/ERK pathway by other growth factors attenuates TGFP signalling.

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