Academic journal article Genetics

Global Regulation of a Differentiation MAPK Pathway in Yeast

Academic journal article Genetics

Global Regulation of a Differentiation MAPK Pathway in Yeast

Article excerpt

Cell differentiation is the process by which cells undergo specialization to produce different cell types with differ- ent functions. Cell-type specialization can result from execu- tion of an intrinsic developmental program and also in response to extrinsic cues. The process of cell differentiation is one of exquisite precision: cells undergo complete mor- phogenetic restructuring in a specific spatiotemporal context (Kholodenko et cd. 2010). Multiple signaling pathways col- laborate to control cell differentiation responses. For exam- ple, the activity of the Wnt and Hippo pathways is integrated at multiple levels to coordinate development (McNeill and Woodgett 2010). A critical problem in the field of cell differ- entiation is to elucidate how signals from different pathways become integrated to produce a cohesive response. This prob- lem is relevant from the standpoint of human health, because misregulation of differentiation pathways is an underlying cause of developmental problems and diseases such as cancer (Wagner and Nebreda 2009).

Depending on ploidy and growth condition, the budding yeast Saccharomyces cerevisiae can differentiate into different cell types. Haploid yeast undergoes morphological changes in response to secreted pheromones to mate and form diploids (Bardwell 2005; Dohlman and Slessareva 2006; Merlini et al. 2013). Diploid yeast starved for carbon and nitrogen initiate a meiotic program known as sporulation (Neiman 2011). Haploid and diploid yeast starved for only carbon or nitrogen undergoes filamentous (or invasive/pseudohyphal) growth (Gimeno et al. 1992; Cullen and Sprague 2000, 2012). Dur- ing filamentous growth, major changes occur to cell polarity (Gimeno et aL 1992; Roberts and Fink 1994; Pruyne and Bretscher 2000; Cullen and Sprague 2002; Bi and Park 2012), cell-cycle progression (Krön et al. 1994; Edgington et al. 1999), and cell adhesion (Lambrechts et al. 1996; Lo and Dranginis 1998; Guo et aL 2000), which results in for- mation of branched chains of interconnected invasive fila- ments. Filamentous cells form complex communities during biofilm formation (Reynolds and Fink 2001; Verstrepen and Klis 2006; Bojsen et al. 2012). Many fungal species undergo filamentous growth. In pathogens, differentiation to filamen- tous/hyphal cells in biofilms is critical for pathogenicity (Lo et al 1997; Wendland 2001; Nobile et al 2006; Sohn et al 2006). Budding yeast therefore provides a convenient genetic system to define the pathways that regulate filamentous growth and has provided insights into the genetic basis of fungal path- ogenesis and eukaryotic differentiation.

Signal transduction pathways regulate filamentous growth and control the changes that occur in response to nutrient limitation (Zhao et al. 2007). Among the pathways that regulate filamentous growth in yeast is a MAPK path- way called the filamentous growth MAPK pathway (Supporting Information, Figure 1A). MAPK pathways are evolutionary con- served signaling modules that regulate diverse responses in eukaryotes (Raman et al 2007). The filamentous growth MAPK pathway is composed of plasma-membrane sensors (Msb2p, Sholp, and Opy2p) (O'Rourke and Herskowitz 1998; Cullen et al. 2004; Wu et al 2006; Yamamoto et al 2010; Karunanithi and Cullen 2012) that connect to a Rho-type GTPase (Cdc42p; Bi and Park 2012) and a kinase cascade consisting of a p21- activated kinase (Ste20p; Peter et al 1996; Leberer et al 1997) and MAPK module (including the MAPKKK Stellp, MAPKK Ste7p, and MAPK Ksslp; Roberts and Fink 1994). The MAP kinase Ksslp regulates the activity of two transcription factors (Stel2p and Teclp; Madhani and Fink 1997; Madhani et al 1997) that induce target genes (Madhani et al. 1999) by bind- ing to well-defined promoter elements (Zeiüinger et al. 2003; Chou et al 2006).

In addition to the MAPK pathway, other pathways al- so regulate filamentous growth. Major nutrient regulatory pathways include the Ras2p-cAMP-protein kinase A (PKA) pathway (Toda et al 1985; Gimeno et al 1992; Mosch et al 1996; Colombo étal. …

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