Interaction of STAT Signals with Other Signaling Pathways

Abstract

Since the discovery of the STAT proteins, there have been a great many reports on the involvement of STAT signals with other signaling pathways. These interactions can be classified into at least four general groups. First, STAT-mediated signals may be the means of the transcriptional upregulation of genes that impact on other pathways. Second, STATs interact with other transcriptional regulators at the promoter level. These interactions occur as STATs bind regions of DNA that are adjacent to or overlap with binding sites for other transcription factors. Moreover, STATs contain binding sites for a number of different co-activators such as the CREB binding protein (CBP) that enables the indirect association with many other transcriptional regulators such as those involved in TGF-β signaling. Third, STAT function can be manipulated by post-translational modification induced by other signaling pathways. An example of such is serine phosphorylation that can be induced by kinases that are activated by other signaling pathways (i.e. TNF-α and IL-1β). And fourth, STATs have been shown to interact with components from other signaling pathways that are not linked to DNA binding or transcription, such as the TNF Receptor 1 (TNFR1) the TNF-Associated Death Domain protein (TRADD). Demonstration of these interactions has provided clues to the mechanisms involved in how cells can integrate multiple signals and respond in a specific manner to a given set of signals from the environment. This chapter will review the interactions of various STAT molecules with signaling components from the TNF, IL-1β, TGF-β and hormone receptor signaling pathways. Specifically, the focus will be on STAT interactions with NF-кB, TNFR1, TRADD, SMADs and glucocorticoid receptor. Since this is not a comprehensive outline of all of the interaction partners of the STATs, emphasis will be placed on the general modes of interaction and the relation to functional modification.