MAPK Pathway in Fission Yeast
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MAPK Pathway in Fission Yeast

In both Prokaryotes and Eukaryotes, a major adaptive response to various Stress conditions is to change the repertoire of Gene expression. Prokaryotic cells commonly employ the two-component Signal Transduction Systems, where a “sensor” Histidine Kinase, often located in the Plasmamembrane, mediates environmental signals to a cytoplasmic “response regulator” that controls transcription of the target gene. Although Homologous mechanisms have been found also in some Eukaryotic organisms, recent studies have uncovered a pivotal role of MAPK (Mitogen-Activated Protein Kinase) Cascades in stress signaling of Yeast and Vertebrate cells. Each MAPK Cascade comprises a series of three or more protein kinases, each phosphorylating and thereby activating the next in line. The last Kinase of the series (the MAPK) is activated by dual phosphorylation on a specific Threonine and a specific Tyrosine residue. A single residue separates the two activating phosphorylation sites, and the Thr-Xaa-Tyr activation motif is a hallmark of MAPKs. Both residues are phosphorylated by a single activating kinase, the MAPKK (Mitogen-Activated Protein Kinase Kinase), which is activated in turn by phosphorylation on one or more serine or threonine residues by a MAPKKK (Mitogen-Activated Protein Kinase Kinase Kinase). There is some cross-talk between pathways, but MAPK Cascades appear to be insulated from each other by the intrinsic specificity of the MAPKKs and MAPKKKs, and possibly by binding interactions that may organize the cassettes into multienzyme complexes. In Fission Yeast, Schizosaccharomyces.pombe, three distinct MAPK pathways have been identified. These include the Mating Pheromone-responsive Spk1 MAPK pathway, the stress-sensing Sty1/Spc1/Phh1 MAPK pathway, and the Pmk1/Spm1 MAPK pathway, which regulates Cell integrity (Ref.1).

The first MAPK Cascade to be discovered in fission yeast was Spk1. This Cascade is required for Mating and Sporulation and includes the MAP kinase Spk1, the MAPKK Byr1, the MAPKKK Byr2 and the small GTPase, Ras1. S. pombe has two types of Pheromone Receptors, the receptor for M-factor and the receptor for P-factor, encoded by two genes, Map3 and Mam2, respectively. When a Mating Pheromone binds to its Serpentine Receptor (Mam2 or Map3), Ras1 activates a MAPK module composed of Byr2, Byr1, and Spk1 protein kinases in concert with a Heterotrimeric G-protein Alpha-subunit, GPA1. Fission yeast possesses two genes encoding Heterotrimeric G protein Alpha-subunits, GPA1 and GPA2, and one gene, GPB1, encoding a Beta-subunit. GPB1 is responsible for Pheromone-responsive Sexual development, and GPA2 relays the nutritional status information necessary to initiate the Sexual differentiation of S. pombe. The G-Beta subunit, GPB1, functions as a negative factor in Sexual development. In S. pombe, it is the G-Alpha subunit that transmits the signal (Ref.2). Differentiation of fission yeast into mating competent cells is strictly dependent on nutritional starvation. The S. pombe Ras homolog Ras1 plays a role in the starvation-dependent control of the mating pathway, possibly in a G-Alpha-independent manner. The Spk1 cascade regulates expression of genes such as Mat1-Pm that are required for conjugation and for induction of Meiosis in diploids. Surprisingly, the transcription of another Pheromone-induced gene, Mam2, depends on Byr1 and Byr2 but not Spk1. Therefore, potentially there is another Byr1- and Byr2-dependent MAP kinase in S.pombe which is required for Mam2 expression and consequently for mating (Ref.3).

Spc1 in Schizosaccharomyces pombe is a member of the Stress-Activated Protein Kinase family, an evolutionary conserved subfamily of MAPKs. Spc1 (also known as Sty1 and Phh1) is identified as a regulator of the Osmotic Response and Cell Cycle. Many different forms of Stress including High Osmolarity, Oxidative Stress, Heat Shock, UV irradiation, and Nutritional Limitation activate Spc1. Spc1 plays a crucial role in Cell Survival under these stress conditions. Spc1 is activated by the Wis1 MAPK kinase, which is in turn activated by two MAPK kinase kinases, Wak1 (also known as Wik1 and Wis4) or Win1. In addition to its role as a component of a Stress-responsive pathway, Wis1 is required for transcriptional induction of two genes (Fbp1 and Mei2) by starvation conditions, a process that is mediated by the cAMP-PKA signaling pathway. Wis1-Sty1 pathway and the cAMP (Cyclic Adenosine Monophosphate)-PKA (Protein Kinase-A) pathway interact and play different roles in regulating Gene Expression and Sexual Development in S. pombe. Spc1 may normally induce gene expression through the Transcription factors Atf1 and Pcr1 and induction of Ctt1 upon Osmostress. A key substrate of Spc1 is the bZIP transcription factor Atf1/Gad7, which is most homologous to mammalian ATF2 (Activating Transcription Factor-2). Activated Atf1 induces transcription of various stress response genes. Atf1 is also responsible for stress-induced expression of the Pyp2 Tyrosine Phosphatase and a type 2C Serine/threonine Phosphatase, Ptc1. Pyp2 dephosphorylates the activating tyrosine phosphorylation in Spc1, and Ptc1 negatively regulates Atf1-dependent transcription of Stress-response genes, which constitutes dual loops of negative feedback. Atf1 is not the sole target of Spc1 because the G2-M Cell Cycle regulation carried out by Spc1 is independent of Atf1. Heat stress also activates Spc1 by a pathway that is independent of MEKKs. It was recently found that heat stress activated Spc1 by inhibition of the Tyrosine Phosphatase Pyp1. Similarly, in response to oxidative stress, MPR1 binds to the MCS4 response regulator that function upstream of the Spc1 cascade, suggesting that MCS4 is a cognate response regulator for MPR1.Thus, Osmotic and Oxidative stress activates Spc1 by different MEKK-dependent processes, whereas heat shock activates Spc1 by a novel mechanism that does not require MEKK activation or Pyp1 inhibition (Ref.4).

A third MAP kinase, Spm1 (S.pombe MAPK)/Pmk1, is recently been discovered in S.pombe. Pmk1 is a MAPK that regulates Cell Integrity and which, with Calcineurin Phosphatase, antagonizes Chloride homeostasis in Fission Yeast. Spm1 is activated by Hypertonic Stress.  Pek1 is a MAPKK for Pmk1 MAPK. Pek1, in its unphosphorylated form, acts as a potent negative regulator of Pmk1 MAPK signaling. Mkh1, an upstream MAPKK kinase (MAPKKK), converts Pek1 from being an inhibitor to an activator. Thus Pek1 has a dual stimulatory and inhibitory function, which depends on its phosphorylation state. This switch-like mechanism could contribute to the all-or-none physiological response mediated by the MAPK signaling pathway (Ref.5). Thus Pmk1 pathway seems to act closely with Ca2+ signaling pathways, in a parallel or dependent manner with respect to the PKC homologs Pck1 and Pck2 and in an opposing manner to calcineurin. Disruption of the Calcineurin gene (Ppb1) in Fission Yeast results in a drastic Cl- (Chloride ion) -sensitive growth defect and a high copy number of a novel gene Pmp1 suppresses this defect. Pmp1 negatively regulates Pmk1 MAP kinase by direct dephosphorylation. Moreover, Pmp1 and Calcineurin Phosphatases share an essential function in Cl- homeostasis, Cytokinesis and Cell Viability. Thus the Calcineurin-mediated pathway and the MAP kinase-signaling pathway play antagonistic roles. Because stress responses involve evolutionarily conserved signaling pathways, S. pombe presents a useful model for the way in which cells sense and respond to stress in other systems (Ref.6).