Filamentation and Invasion Pathway in Budding Yeast
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Filamentation and Invasion Pathway in Budding Yeast
Vegetative yeast cells respond to environmental cues by activating signal transduction pathways that enable them to mount the appropriate physiological response. Each of the cues is dealt with by distinct signaling mechanisms to cause the appropriate response to a given stimulus. In the budding yeast Saccharomyces cerevisae, there are at least five MAP kinase (Mitogen-Activated Protein Kinase) cascades. MAPK cascades are conserved signaling modules that regulate responses to diverse extracellular stimuli, developmental cues and environmental stresses. A MAPK is phosphorylated and activated by a MAPKK (MAPK Kinase), which is activated by an upstream protein kinase, MAPKK kinase. Each pathway is initiated by a distinct upstream regulator and individual MEKK-MEK-MAPK modules control mating, cell-wall integrity, pseudohyphal development and filamentous invasive growth, sporulation and osmoregulation (Ref.1).

Nitrogen starvation induces filamentation and invasion in budding yeast. In response to starvation, yeast undergoes dramatic morphological changes involving pseudohyphal formation and invasiveness in an attempt to find nutrients that are controlled in part by a MAPK pathway. When starved for nitrogen, the elliptical diploid yeast undergoes an asymmetric cell division to produce a long thin daughter cell that will keep producing long daughter cells. Because the mother and daughter cells remain attached, reiteration of this unipolar division pattern produces filaments composed of a linear chain of elongated cells called a pseudohypha. A related phenomenon, invasive growth, occurs in haploid cells on rich medium. The signaling pathway that triggers invasive growth in haploid cells utilizes Ste20, Ste7, Ste11, and Ste12. Filamentous or pseudohyphal growth in diploid S. cerevisiae cells is characterized by cell elongation, amitotic delay, symmetric cell division, unipolar budding and persistent physical attachment of mother and daughter cells. In comparison to diploid cells, dimorphic switching in haploid S. cerevisiae is subtler, leading to increased cell–cell adhesion but only limited changes in cell morphology. Other signals such as poorly utilized carbon sources also induce filamentous growth. In addition to nitrogen and carbon starvation, oxygen limitation may also affect dimorphic switching in both haploids and diploids (Ref.2).

Filamentous invasive growth of S. cerevisiae requires multiple elements of the MAPK signaling cascade that are also components of the mating pheromone response pathway. The MAPK cascade mediates signal transduction in filamentation-invasion pathway from two small GTP binding proteins, Ras2 and CDC42 (Cell Division Cycle-42). Signaling from Ras2 requires the 14-3-3 proteins BMH1 (Brain Modulosignalin Homolog-1) and BMH2(Brain Modulosignalin Homolog-2) and possibly Sho1 receptor. CDC42 acts downstream of Ras2 and is required for the function of the PAK Ste20 in the filamentation-invasion pathway. CDC42-Ste20 then transmits signal to the MAPK cascade. Like the Pheromone response pathway, this cascade contains the MEKK Ste11 and the MEK Ste7. However, the MAPK for the filamentation-invasion pathway is Kss1, in place of Fus3. Also, the pheromone response pathway has Ste5 as a scaffold for the MAPK cascade while a MAPK cascade scaffold protein for the filamentation- invasion pathway has yet to be uncovered. The filamentation-invasion pathway, like the pheromone response pathway, regulates transcription. The MAPK Kss1 has a dual role in regulating filamentous invasive growth of the yeast Saccharomyces cerevisiae. The stimulatory function of Kss1 requires both its catalytic activity and its activation by the MEK (MAPK/ERK kinase) Ste7; in contrast, the inhibitory function of Kss1 requires neither. Unphosphorylated Kss1 binds directly to the transcription factor Ste12 and forms a protein complex that also contains Tec1, and the inhibitory proteins Dig1 or Dig2. Upon phosphorylation through a MAPK cascade, Kss1 dissociates from the complex, thereby destabilizing the Ste12-Dig association. Activated Kss1 phosphorylates and activates Ste12, leading to binding of Ste12 in combination with Tec1 to genes containing a Ste12/Tec1 composite binding site, referred to as a FRE (Filamentous and invasive growth Response Element). FRE, a combination of TCS (TEA/ATTS Consensus Sequence) and PRE (Pheromone Response Element), mediates the binding of the heterodimer formed by the association of the transcriptional activators Tec1 and Ste12. Thus, the MAPK Kss1 plays a key role in the transcriptional control of genes regulated by FRE both by derepression and activation (Ref.3). Relative to Kss1, the MAPK Fus3 binds less strongly to Ste12 and is correspondingly a weaker inhibitor of invasive growth. Potent repression of a transcription factor by its physical interaction with the inactivated isoform of a protein kinase, and relief of this repression by activation of the kinase, is a novel mechanism for signal-dependent regulation of gene expression. In the absence of Fus3, the invasive growth pathway MAP kinase Kss1 is inappropriately activated by the mating signaling pathway, leading to transcription of both mating-specific genes and invasive growth genes. Spa2 and Sph1 may also be involved in localizing MAPK signaling during pseudohyphal growth. Sph1 interacts with Ste7 and Ste11, suggesting that the polarization effects of these proteins may be due to localized MAPK signaling (Ref.4).

S. cerevisiae provides a genetically suitable organism for studying dimorphism of fungal organisms. Pathways and processes identified and characterized in S. cerevisiae will no doubt advance our understanding of analogous regulation of morphogenesis and pathogenicity in other organisms. Major challenges still remain in determining how cells sense filamentous growth signals from their environment, how various signaling cascades process and integrate filamentous growth signals, and how these signals manifest in physical processes leading to filament formation. At the signaling level, new strategies to identify nonlinear complexities in signal transduction, such as crosstalk and feedback loops, must be developed. Finally, an integrated model of how cell attachment, shape and budding polarity are regulated by these signaling pathways will lead to a better understanding of filamentous and invasive growth (Ref.5).