Control of yeast filamentous-form growth by modules in an integrated molecular network

The availability and maturation of high-throughput biotechnologies is transforming the way cellular systems are studied. Our expanding genome-scale understanding suggests a hierarchical view of the cell in which groups of interacting molecules form biological modules, and biological modules interact in complex networks that control the properties of a cell. By traversing this hierarchy, biologists can discover properties of cells responding to perturbations or stimuli, and formulate molecular hypotheses on the control of cell properties such as metabolic capabilities, cell-cycle progression, and cell morphology. A key intermediate level in the organizational hierarchy is the module. Biological modules are loose associations of preferred molecular interaction partners that interact to perform a collective function (Hartwell et al. 1999). These loose molecular associations can be identified based on structural characteristics such as their closely connected members (Ravasz et al. 2002; Rives and Galitski 2003) and interfaces to other modules (Girvan and Newman 2002). In addition, there is evidence that modules are evolutionarily conserved (Snel et al. 2002), and that module co-members tend to be coordinately expressed (Ihmels et al. 2002; Segal et al. 2003). Applying module-level network analysis to several integrated genome-scale data sets, we studied a complex network controlling the differentiation of budding-yeast cells into a filamentous form. This approach implicated numerous module-associated biological processes in filamentous-form growth. Various fungi, including major pathogens, can transform from a cellular yeast form to an invasive filamentous form in a morphogenetic program initiated by environmental stimuli (for review, see in Lengeler et al. 2000). For budding-yeast MATa/α diploid cells, low availability of ammonium and a solid growth substrate trigger the dimorphic switch to filamentous-form growth, characterized by cell elongation, unipolar distal budding, adhesion, and invasion (Gimeno et al. 1992; Kron et al. 1994). This transformation is often referred to as pseudohyphal development. Here it is referred to as filamentous-form growth. Several conserved signaling pathways that regulate this process have been intensively studied. Most prominent among these are the cAMP-dependent protein–kinase-A pathway, and the filamentation mitogen-activated protein–kinase pathway (fMAPK; for review, see Gancedo 2001). In addition, as in the yeast-form mitotic cell cycle (Lew and Reed 1995), Cdc28 kinase activity controls cell-cycle progression and morphogenesis during filamentous-form growth (for review, see Rua et al. 2001). The G1 cyclin Cln1 is required for polarized growth and is transcriptionally induced by enhanced fMAPK activity (Loeb et al. 1999; Madhani et al. 1999). In addition, the stability of the Cln1 protein is controlled by phosphorylation-dependent ubiquitination by the SCF ubiquitin-ligase (Skowyra et al. 1999). The present work implicates the subsequent step, ubiquitin-dependent protein degradation by the 26S proteasome, in the control of filamentous-form growth.