Spatial and temporal organization of signaling pathways

Abstract

The development and maintenance of the many different cell types in metazoan organisms requires robust and diverse intercellular communication mechanisms. Relatively few such signaling pathways have been identified, leading to the question of how such a broad diversity of output is generated from relatively simple signals. Recent studies have revealed complex mechanisms integrating temporal and spatial information to generate diversity in signaling pathway output. We review some general principles of signaling pathways, focusing on transcriptional outputs in Drosophila. We consider the role of spatial and temporal aspects of different transduction pathways and then discuss how recently developed tools and approaches are helping to dissect the complex mechanisms linking pathway stimulation to output.

Keywords: crosstalk; signaling dynamics; signaling pathways.

Figure 1

Signaling pathways produce distinct transcriptional outputs. Signaling pathways can produce distinct transcriptional outputs by binding to the regulatory sequences of different genes. Oval shapes labeled 1 and 2 represent transcription factors regulated downstream of signals A and B, respectively, and their effects on three classes of genes (blue lines) are illustrated. Arrows indicate gene activation and crosses represent the lack of activation. In some cases a single signal may be sufficient; in the first two examples, binding of transcription factor 1 or 2 is sufficient to activate the top or bottom target gene respectively. In other cases combinatorial inputs may be required for activation; in the third example, both transcription factors must be bound for activation of the middle gene. This leads to diversity of signaling outputs depending on the signaling contexts in which a pathway is activated.

Figure 2

Signaling pathway output depends on context. Circles represent the transcriptional potential of cells, which is initially unrestricted (white circle). As cells experience signaling events, the transcriptional potential becomes partially restricted (gray shading), providing a contextual background in which subsequent signaling is interpreted (i.e., the history of the cell). Signaling pathways then act on this limited set of accessible genes to further define the transcriptional profile (signals A, B, or A + B lead to profiles 1, 2, or 3 respectively). As illustrated in Figure 1, different signaling pathways or combinations of pathways will lead to distinct but possibly overlapping transcriptional profiles (red, blue, and green shading).

Figure 3

Four classes of signaling pathways with different transduction mechanisms. Signaling pathways can be broadly classified based on the complexity of their signal transduction mechanisms. Hormone pathways are relatively simple, with few components. A ligand (green) interacts with a receptor (orange) that also functions as a transcription factor, thereby generating a direct link between the signal and a transcriptional effect. The Notch pathway illustrates a more complex class of signaling, with the receptor (orange) and transcription factor (pink) acting as separate components. The JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway has a further increase in complexity, with the recruitment of a signal transduction component (purple) between the receptor and transcription factor. Regulation of this transduction component by phosphorylation generates an additional level at which cross-regulation with other pathways can occur. Finally, RTKs (receptor tyrosine kinases) are the most complex class of signaling pathways, with multiple parallel transduction pathways. Many of these pathways are likely ineffective in a given context (gray arrows), and productive responses (black arrows) are defined by the components present (history of the cell) and inputs from other pathways (crosstalk). As signaling pathway complexity increases, opportunities for crosstalk with other pathways increase, as well leading to potentially new outputs.

Figure 4

Mechanisms of crosstalk. Depending on the category of pathways used, communication between pathways can occur at different levels. (A) Integration of transcription factors (blue, red, and purple shapes) at the enhancer level (all pathways). (B) Direct crosstalk between components of the transduction machinery can lead to activation of different transcription factors (TF) and/or the use of different transduction pathways (black arrows represent active transduction pathways, gray arrows represent inactive transduction pathways). This is more likely with increased pathway complexity. (C) Sequential activation of pathways (possible for all pathways). Note that sequential activation of pathways can be difficult to distinguish from simultaneous signaling, depending on the assays and tools used to monitor pathway activity.