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Title: Multiple Signals Converge on a Differentiation MAPK Pathway}
Article:
Abstract:
An important emerging question in the area of signal transduction is how information from different pathways becomes integrated into a highly coordinated response. In budding yeast, multiple pathways regulate filamentous growth, a complex differentiation response that occurs under specific environmental conditions. To identify new aspects of filamentous growth regulation, we used a novel screening approach( called secretion profiling) that measures release of the extracellular domain of Msb2p, the signaling mucin which functions at the head of the filamentous growth( FG) MAPK pathway. Secretion profiling of complementary genomic collections showed that many of the pathways that regulate filamentous growth( RAS, RIM101, OPI1, and RTG) were also required for FG pathway activation. This regulation sensitized the FG pathway to multiple stimuli and synchronized it to the global signaling network. Several of the regulators were required for MSB2 expression, which identifies the MSB2 promoter as a target “hub” where multiple signals converge. Accessibility to the MSB2 promoter was further regulated by the histone deacetylase( HDAC) Rpd3p( L), which positively regulated FG pathway activity and filamentous growth. Our findings provide the first glimpse of a global regulatory hierarchy among the pathways that control filamentous growth. Systems-level integration of signaling circuitry is likely to coordinate other regulatory networks that control complex behaviors.
Introduction:
Signal transduction pathways regulate the response to extracellular stimuli. Complex behaviors frequently require the action of multiple pathways that act in concert to reprogram cell fate. In metazoan development for example, a highly regulated network of interactions between evolutionarily conserved pathways like Notch and EGFR coordinates every facet of cell growth and differentiation[1]. An important question therefore is to understand how different pathway activities are coordinated during complex behaviors. Addressing this question is increasingly problematic because signaling pathways operate in vast interconnected web-like information networks[2]. Miscommunication between pathways is an underlying cause of diseases such as cancer[3], and therefore it is both critically important and extremely challenging to precisely define the regulatory connections among signaling pathways. The budding yeast Saccharomyces cerevisiae undergoes a variety of different responses to extracellular stimuli as a result of the function of evolutionarily conserved signal transduction pathways. In response to nutrient limitation, yeast undergoes filamentous growth[4],[5],[6], a cellular differentiation response in which changes in polarity, cell-cycle progression, and gene expression induce the formation of branched chains of interconnected and elongated filaments. The filamentous cell type is widely regarded as a model for differentiation[7],[8],[9],[10], and in pathogens like Candida albicans, filamentous growth is a critical aspect of virulence[11],[12],[13]. A number of different pathways are required for filamentous growth( Figure 1A, left panel). These include a MAPK pathway commonly referred to as the FG pathway( Figure 1A, right panel[14],[15],[16]), the RAS pathway[4],[17], the target of rapamycin or TOR pathway[18], the RIM101 pathway[19],[20],[21], the retrograde pathway( RTG[7]), the inositol regulatory transcription factor Opi1p[22], and a global glucose control protein kinase Snf1p[23],[24],[25]. It is not clear whether these different pathways function together or independently to regulate filamentous growth. This question is compounded by the fact that several hundred other proteins have been implicated in the filamentation response[7],[26],[27]. To identify new aspects of filamentous growth regulation, we developed a screening approach to identify regulators of the MAPK pathway that controls filamentous growth. The FG pathway is regulated by the signaling mucin Msb2p[28], a cell-surface glycoprotein[29] that mediates signaling through the RHO guanine nucleotide triphosphatase( GTPase) Cdc42p[30]. Msb2p is processed in its extracellular domain by the aspartyl protease Yps1p, and release of the extracellular domain is required for FG pathway activation[31]. By measuring release of the extracellular domain of Msb2p in complementary genomic collections, we identified new regulators of the FG pathway. Unexpectedly, many of the major filamentation regulatory pathways( RAS, RIM101, OPI1, and RTG) were found to be required for MAPK activation. Our study indicates that the pathways that control filamentous growth are connected in co-regulatory circuits, which brings to light a systems-level coordination of this differentiation response.
Discussion:
We specifically show that four major regulators of filamentous growth are also required for FG pathway signaling( Figure 5E). The connections between the RIM101, OPI1, and RTG pathways to FG pathway regulation are entirely novel. We further show that the RAS pathway and several other pathways[MAPK, Swi4p, Rpd3p( L)] converge on the promoter of the key upstream regulator( MSB2) of the FG pathway. Like other signal integration mechanisms[8],[66], the MSB2 promoter is a target “hub” where multiple pathways converge. This regulatory point makes sense from the perspective that Msb2p levels dictate FG pathway activity[28]. Given that the FG pathway exhibits multimodality in regulation of pathway outputs[39], its precise modulation is critical to induce an appropriate response. The regulation of the FG pathway differs from that of a related MAPK pathway, the pheromone response pathway, where secreted peptide pheromones provide the single major input into activation[5],[106],[107]. The pheromone response pathway is not regulated by the RAS, RIM, or RTG pathways and does not appear to be influenced by the Rpd3p( L) HDAC, although some target mating genes do require Rpd3p( L) for expression[100]. Both the FG and mating pathways are regulated by positive feedback[28],[65],[108],[109], presumably to provide signal amplification. Therefore, the FG pathway is distinguished in that it is highly sensitized to multiple external inputs. Because our screening approach was highly biased to identify regulators that function at the “top” of the pathway( at Msb2p), it is likely that the FG pathway may be subject to additional regulation not identified by this approach. The networks that regulate filamentation signaling pathways appear in some cases to be redundant. For example, RAS regulates FLO11 expression through Flo8p and the FG pathway( Figure 5E). RIM101 similarly controls FLO11 expression through Nrg1p/Nrg2p and FG regulation( Figure 5E). However, any one of the major filametation regulatory pathways when absent appears fully defective for the response. Such parallel processing of signaling networks might allow for “fine-tuning” of the differentiation response, or alternatively to synchronize all of the pathways to the global regulatory circuit. Such synchronization may coordinate different aspects of filamentous growth( cell-cell adhesion, cell cycle regulation, reorganization of polarity) into a cohesive response. Filamentous growth occurs within a narrow nutritional range[25], between high nutrient levels that support vegetative growth and limiting nutrients that force entry into stationary phase. The finding that Ras2p controls the overall levels of MSB2 expression extends the initial connection between RAS and the FG pathway[61] in several important ways. First, the results explain how Ras2p connects to the FG pathway above Cdc42p. Second, the data provide a link between nutrition and FG pathway signaling at the level of cellular cAMP levels. Third, Ras2p does not appear to function as a component of the FG pathway. This conclusion is based on the conditional requirement for Ras2p in MSB2 regulation, the suppression of the ras2Δ signaling defect by loss of PDE2, and the placement of Ras2p above MSB2 in the FG pathway. Our results fit with the general idea that RAS controls a broad response to cellular stress that encompasses FG pathway regulation. Ras2p has recently been shown to regulate the MAPK pathway that controls sporulation[110], a diploid-specific starvation response. Ras2p may therefore function as a general regulator of MAPK signaling in response to nutritional stress. Examples by which MAPK pathways control target gene expression by recruitment of chromatin remodeling proteins is relatively common and include Rpd3p( L) regulation of HOG[99],[111],[112] and mating pathway[100] target genes. However, the regulation of MAPK activity through chromatin remodeling proteins provides a hierarchical mechanism for global cellular reprogramming. Regulation of FG pathway activity by Rpd3p( L) may contribute to the establishment of a differentiated state. Once activated, FG pathway activity may be sustained by Rpd3p( L) to reinforce accessibility to the MSB2 promoter and formation of the filamentous cell type. Although the connection between Rpd3p( L) and nutrition is not entirely clear, Rpd3p( L) preferentially localizes to highly expressed genes, such as those required for anabolic processes[113]. Therefore, Rpd3p( L) may coordinate overall growth rate with the persistence of MAPK activity. Precedent for Rpd3p( L) HDACs in regulating developmental transitions comes from Drosophila DRpd3, which together with the Chameau HAT function as opposing cofactors of JNK/AP-1-dependent transcription during metamorphosis[114]. HDAC regulation of MAPK activity may therefore represent a general feature of MAPK regulation. In conclusion, we have identified an unprecedented degree of regulation of a differentiation-dependent MAPK pathway by multiple regulatory proteins and pathways. Our findings open up new avenues for exploring the relationships between pathways and the extent of their cross-regulation with the ultimate goal of understanding all functionally relevant pathway interactions in a comprehensive manner.
Signal integration is an essential feature of information flow through signal transduction pathways . The mechanisms by which signals from multiple pathways become integrated into a coordinated response remain unclear . We show that multiple pathways that regulate filamentous growth converge on a differentiation-dependent MAPK pathway . Our findings indicate that more extensive communication occurs between signaling pathways that control the filamentation response than has previously been appreciated . We suggest that global communication hierarchies regulate information flow in other systems , particularly higher eukaryotes where multiple pathways typically function simultaneously to modulate a complex response .