Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation

Cellular differentiation, mating, and filamentous growth are regulated in many fungi by environmental and nutritional signals. For example, in response to nitrogen limitation, diploid cells of the yeast Saccharomyces cerevisiae undergo a dimorphic transition to filamentous growth referred to as pseudohyphal differentiation. Yeast filamentous growth is regulated, in part, by two conserved signal transduction cascades: a mitogen-activated protein kinase cascade and a G-protein regulated cyclic AMP signaling pathway. Related signaling cascades play an analogous role in regulating mating and virulence in the plant fungal pathogen Ustilago maydis and the human fungal pathogens Cryptococcus neoformans and Candida albicans. We review here studies on the signaling cascades that regulate development of these and other fungi. This analysis illustrates both how the model yeast S. cerevisiae can serve as a paradigm for signaling in other organisms and also how studies in other fungi provide insights into conserved signaling pathways that operate in many divergent organisms.

Signal Transduction Cascades Regulating Fungal Development and Virulence

MAP kinases (MAPKs) and their upstream regulatory ki- nases comprise a functional unit that couples upstream input signals to a variety of outputs (reviewed by Blenis, 1993; Blumer and Johnson, 1994; Marshall, 1994). The defining characteristic in this module is the MAPK itself (also called ERK). It has a regulatory kinase, MAPK kinase or MEK (for MAPK/ERK kinase), necessary for its activa- tion. This enzyme is, in turn, regulated by another kinase-- raf, mos, or a group of structurally related kinases termed MEKK (for MEK kinase). Raf is found widely in metazoans and is the upstream member of the raf-MEK-MAPK mod- ule (Figure 1). Budding yeast lacks raf but has two identi- fied MEK kinases, STE11 and BCK1, which are structur- ally related to a mammalian MEKK (Lange-Carter et al., 1993). I shall refer to this structurally related group of ki- nases as the MEKK family. Members of this family have also been identified in tobacco (NPK1; Banno et al., 1993) and in fission yeast (byr2; Wang et al., 1991). These en- zymes are upstream components of the MAPK module MEKK-MEK-MAPK (Figure 1). A recent flurry of activity has revealed the manner in which the raf-MEK-MAPK module is regulated by coupling to membrane receptors 'in a process involving ras and its regulator SOS (reviewed by Blenis, 1993). Little is known in metazoan systems about how MEKK is regulated and about how receptors other than those involving tyrosine kinases feed into MAPK modules. The budding yeast Saccharomyces cerevisiae has at least six identified pathways that contain MAPKs or their presumed upstream regulators. Studies of these different pathways are providing a wealth of information on different possible inputs to MEKK-MEK-MAPK modules (from ser- pentine receptors and perhaps from two-component regu- latory systems) and on new components that play im- portant roles in the MEKK-MEK-MAPK module and are likely to be found in metazoans (Figure 1). In particular, recent work has revealed the existence of an intriguing novel component, STE5, which appears to be a scaffold for association of the three protein kinases in the MEKK- MEK-MAPK module of the yeast pheromone response pathway. This pathway also contains yet another protein kinase, STE20, which likely functions upstream of the MEKK as a link to the G protein. The existence of mamma- lian homologs of STE20 (p65 PAK) raises the possibility that STE20 relatives might also regulate mammalian MEK ki- nases. The MEKK-MEK-MAPK modules of budding yeast are involved in a wide variety of biological processes: they govern transitions in its life cycle--mating and invasive- ness in haploid strains and pseudohyphal development and spore formation in diploid strains--as well as mainte- nance cell wall integrity and response of cells to high osmolarity. A well-studied MAPK module of the fission yeast Schizosaccharomyces pombe is involved in mating and other steps in its life cycle, and an element of a MAPK module has been found in the fungal plant pathogen Usti- lago maydis, where it may play a role in responding to signals from its host plant. One of the purposes this review is to describe the components of these MAPK path- ways and to place them in biological context. Studies with these organisms present an opportunity to use facile ge- netic analysis to identify components of these pathways and to determine whether they play a role in more than one pathway. These studies reveal a case in which a com- ponent functions in more than one pathway within a given cell type (Roberts and Fink, 1994) two examples in which components are functionally redundant (Elion et al., 1991; Irie et al., 1993). These observations and the fact that a unicellular organism has at least six distinct MAPK pathways raise several questions about the specificity with which the MAPKs are activated. Additional goals of this review are to understand the bases for specificity in different pathways and to highlight some of the new molec- ular insights into these pathways that may be relevant to similar systems in metazoans. The diversity and function of MAPKs in yeast have been the subject of several excel- lent recent reviews (Neiman, 1993; Errede and Levin, 1993; Ammerer, 1994).

https://www.cell.com/cell/pdf/0092-8674(95)90402-6.pdf

MAP Kinase Pathways in Yeast: For Mating and More Review

Many fungal pathogens invade plants using specialized infection structures called appressoria that differentiate from the tips of fungal hyphae contacting the plant surface. We demonstrate a role for a MAP kinase that is essential for appressorium formation and infectious growth in Magnaporthe grisea, the fungal pathogen responsible for rice blast disease. The PMK1 gene of M. grisea is homologous to the Saccharomyces cerevisiae MAP kinases FUS3/KSS1, and a GST-Pmk1 fusion protein has kinase activity in vitro. pmk1 mutants of M. grisea fail to form appressoria and fail to grow invasively in rice plants. pmk1 mutants are still responsive to cAMP for early stages of appressorium formation, which suggests Pmk1 acts downstream of a cAMP signal for infection structure formation. PMK1 is nonessential for vegetative growth and sexual and asexual reproduction in culture. Surprisingly, when expressed behind the GAL1 promoter in yeast, PMK1 can rescue the mating defect in a fus3 kss1 double mutant. These results demonstrate that PMK1 is part of a highly conserved MAP kinase signal transduction pathway that acts cooperatively with a cAMP signaling pathway for fungal pathogenesis.

/pdf/map-kinase-and-camp-signaling-regulate-infection-structure-3o0z6o1bbv.pdf

MAP kinase and cAMP signaling regulate infection structure formation and pathogenic growth in the rice blast fungus Magnaporthe grisea.

Diploid strains of baker9s yeast Saccharomyces cermisiae can grow in a cellular yeast form or in filaments called pseudohyphae. This dimorphic transition from yeast to pseudohyphae is induced by starvation for nitrogen. Not all laboratory strains are capable of this dimorphic switch; many grow only in the yeast form and fail to form pseudohyphae when starved for nitrogen. Analysis of the standard laboratory strain S288C shows that this defect in dimorphism results from a nonsense mutation in the FL08 gene. This defect in FL08 blocks pseudohyphal growth in diploids, haploid invasive growth, and flocculation. Since feral strains of S. cerevisiae are dimorphic and have a functional FL08 gene, we suggest that the fl08 mutation was selected during laboratory cultivation.

https://www.genetics.org/content/genetics/144/3/967.full.pdf

Saccharomyces cerevisiae S288C has a mutation in FLO8, a gene required for filamentous growth.

Ustilago maydis is a plant pathogenic Basidiomycete fungus that exhibits dimorphism--it has a haploid, yeast-like phase and a dikaryotic, filamentous phase that is pathogenic. Establishment and maintenance of these two forms are controlled by two mating type loci, a and b. The a locus is thought to govern fusion of haploid cells to form a dikaryon and is also required for filamentous growth of the dikaryon. It encodes two components of a pheromone response pathway: pheromones and receptors. We report the identification of the U. maydis fuz7 gene, which codes for a putative dual specificity serine/threonine tyrosine kinase of the MAP kinase kinase (MAPKK/MEK) family, by homology with other members of the family. Analysis of mutants deleted for fuz7 shows that it participates in different facets of the life cycle: It is necessary for a-locus-dependent processes, such as conjugation tube formation, filament formation, and maintenance of filamentous growth, and for a-locus-independent processes, such as tumor induction and teliospore germination. fuz7 is the first U. maydis gene distinct from the b locus required for fungal pathogenicity. We propose that fuz7 is involved in at least two pathways, one of which responds to the pheromones coded by the a locus and the other to putative signals from the plant.

/pdf/identification-of-fuz7-a-ustilago-maydis-mek-mapkk-homolog-52zr9yizdy.pdf

Identification of fuz7, a Ustilago maydis MEK/MAPKK homolog required for a-locus-dependent and -independent steps in the fungal life cycle.

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Identification of fuz7, a Ustilago maydis MEK/MAPKK homolog required for a-locus-dependent and -independent steps in the fungal life cycle.