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Multiple crosstalk between TOR and the cell integrity MAPK signaling pathway in fission yeast

View Article: PubMed Central - PubMed

ABSTRACT

In eukaryotic cells, the highly conserved Target of Rapamycin (TOR) and the Mitogen Activated Protein Kinase (MAPK) signaling pathways elicit adaptive responses to extra- and intracellular conditions by regulating essential cellular functions. However, the nature of the functional relationships between both pathways is not fully understood. In the fission yeast Schizosaccharomyces pombe the cell integrity MAPK pathway (CIP) regulates morphogenesis, cell wall structure and ionic homeostasis. We show that the Rab GTPase Ryh1, a TORC2 complex activator, cross-activates the CIP and its core member, the MAPK Pmk1, by two distinct mechanisms. The first one involves TORC2 and its downstream effector, Akt ortholog Gad8, which together with TORC1 target Psk1 increase protein levels of the PKC ortholog Pck2 during cell wall stress or glucose starvation. Also, Ryh1 activates Pmk1 in a TORC2-independent fashion by prompting plasma membrane trafficking and stabilization of upstream activators of the MAPK cascade, including PDK ortholog Ksg1 or Rho1 GEF Rgf1. Besides, stress-activated Pmk1 cross-inhibits Ryh1 signaling by decreasing the GTPase activation cycle, and this ensures cell growth during alterations in phosphoinositide metabolism. Our results reveal a highly intricate cross-regulatory relationship between both pathways that warrants adequate cell adaptation and survival in response to environmental changes.

No MeSH data available.


Cross-regulatory interactions between TOR and cell integrity MAPK signaling in fission yeast.Rab GTPase Ryh1 cross-activates the cell integrity pathway (CIP) through two independent mechanisms. TORC2 target Gad8 cooperates with TORC1 target Psk1 to increase Pck2 protein levels and promote activation of MAPK Pmk1during growth and stress. Alternatively, Ryh1 elicits plasma membrane targeting and/or stabilization of several upstream activators of the CIP (Ksg1 (PDK), Rgf1 (Rho1 GEF), and Pck2). PI kinase Its3 and PI(4,5)P2 promote Ryh1-TORC2 signaling and activation of the CIP, and in this later case might act as Ryh1 effector. In addition, activated Pmk1 decreases TORC2-Gad8 signaling in response to stress by downregulating Ryh1 activation cycle. Coordinated activation/deactivation of TOR and CIP signaling allows precise cell adaptation to multiple environmental cues.
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f8: Cross-regulatory interactions between TOR and cell integrity MAPK signaling in fission yeast.Rab GTPase Ryh1 cross-activates the cell integrity pathway (CIP) through two independent mechanisms. TORC2 target Gad8 cooperates with TORC1 target Psk1 to increase Pck2 protein levels and promote activation of MAPK Pmk1during growth and stress. Alternatively, Ryh1 elicits plasma membrane targeting and/or stabilization of several upstream activators of the CIP (Ksg1 (PDK), Rgf1 (Rho1 GEF), and Pck2). PI kinase Its3 and PI(4,5)P2 promote Ryh1-TORC2 signaling and activation of the CIP, and in this later case might act as Ryh1 effector. In addition, activated Pmk1 decreases TORC2-Gad8 signaling in response to stress by downregulating Ryh1 activation cycle. Coordinated activation/deactivation of TOR and CIP signaling allows precise cell adaptation to multiple environmental cues.

Mentions: Ryh1 regulates the intra-Golgi trafficking and is involved in recycling from endosome to the Golgi, as well as in trafficking events from the Golgi to the plasma membrane232547. Here we obtained strong evidence supporting that Ryh1 controls the activity of the CIP through an additional mechanism independent of its role as an upstream regulator of TORC2 signaling (Fig. 8). This is based in two main findings. First, contrary to control, tor1Δ, or gad8Δ psk1Δ cells, Pmk1 activation in response to a salt stress was strongly defective in ryh1Δ cells. Second, protein levels and/or plasma membrane localization of key upstream regulatory members of the CIP, including PDK ortholog Ksg1, Rho1 GEF Rgf1, Rho GTPases Rho1 and Rho2, and Pck2, are heavily misregulated in ryh1Δ cells with respect to control, tor1Δ, and gad8Δ cells. Consequently, Ryh1 function might be required for proper trafficking of the above signaling proteins to their membrane anchors. Intriguingly, membrane targeting and protein levels of Ksg1, Rho1, and Rho2 were also moderately reduced in tor1Δ and gad8Δ cells, suggesting that TORC2-Gad8 might regulate to some extent plasma membrane trafficking and/or protein stabilization events. In support of this possibility, the plasma membrane localization of the high affinity glucose transporter Ght5 under low-glucose conditions is regulated by TORC2-Gad848. Collectively, our results reveal that Ryh1 positively controls the activation of the CIP via two distinct branches (Fig. 8). One involves proper trafficking and localization of key activators of the CIP, and is particularly relevant during MAPK activation in response to osmotic stress. The second branch is essential during cell wall damage or absence of glucose, and reinforces MAPK activation via TORC2-Gad8 to enhance Pck2 levels. In any case, this novel role of Ryh1 as elicitor of MAPK signaling might not be shared by budding yeast, since deletion of Ypt6 (Ryh1 ortholog) did not impair activation of MAPKs Slt2 and Hog1 in response to different stimuli (Suppl. Figure S7).


Multiple crosstalk between TOR and the cell integrity MAPK signaling pathway in fission yeast
Cross-regulatory interactions between TOR and cell integrity MAPK signaling in fission yeast.Rab GTPase Ryh1 cross-activates the cell integrity pathway (CIP) through two independent mechanisms. TORC2 target Gad8 cooperates with TORC1 target Psk1 to increase Pck2 protein levels and promote activation of MAPK Pmk1during growth and stress. Alternatively, Ryh1 elicits plasma membrane targeting and/or stabilization of several upstream activators of the CIP (Ksg1 (PDK), Rgf1 (Rho1 GEF), and Pck2). PI kinase Its3 and PI(4,5)P2 promote Ryh1-TORC2 signaling and activation of the CIP, and in this later case might act as Ryh1 effector. In addition, activated Pmk1 decreases TORC2-Gad8 signaling in response to stress by downregulating Ryh1 activation cycle. Coordinated activation/deactivation of TOR and CIP signaling allows precise cell adaptation to multiple environmental cues.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5120329&req=5

f8: Cross-regulatory interactions between TOR and cell integrity MAPK signaling in fission yeast.Rab GTPase Ryh1 cross-activates the cell integrity pathway (CIP) through two independent mechanisms. TORC2 target Gad8 cooperates with TORC1 target Psk1 to increase Pck2 protein levels and promote activation of MAPK Pmk1during growth and stress. Alternatively, Ryh1 elicits plasma membrane targeting and/or stabilization of several upstream activators of the CIP (Ksg1 (PDK), Rgf1 (Rho1 GEF), and Pck2). PI kinase Its3 and PI(4,5)P2 promote Ryh1-TORC2 signaling and activation of the CIP, and in this later case might act as Ryh1 effector. In addition, activated Pmk1 decreases TORC2-Gad8 signaling in response to stress by downregulating Ryh1 activation cycle. Coordinated activation/deactivation of TOR and CIP signaling allows precise cell adaptation to multiple environmental cues.
Mentions: Ryh1 regulates the intra-Golgi trafficking and is involved in recycling from endosome to the Golgi, as well as in trafficking events from the Golgi to the plasma membrane232547. Here we obtained strong evidence supporting that Ryh1 controls the activity of the CIP through an additional mechanism independent of its role as an upstream regulator of TORC2 signaling (Fig. 8). This is based in two main findings. First, contrary to control, tor1Δ, or gad8Δ psk1Δ cells, Pmk1 activation in response to a salt stress was strongly defective in ryh1Δ cells. Second, protein levels and/or plasma membrane localization of key upstream regulatory members of the CIP, including PDK ortholog Ksg1, Rho1 GEF Rgf1, Rho GTPases Rho1 and Rho2, and Pck2, are heavily misregulated in ryh1Δ cells with respect to control, tor1Δ, and gad8Δ cells. Consequently, Ryh1 function might be required for proper trafficking of the above signaling proteins to their membrane anchors. Intriguingly, membrane targeting and protein levels of Ksg1, Rho1, and Rho2 were also moderately reduced in tor1Δ and gad8Δ cells, suggesting that TORC2-Gad8 might regulate to some extent plasma membrane trafficking and/or protein stabilization events. In support of this possibility, the plasma membrane localization of the high affinity glucose transporter Ght5 under low-glucose conditions is regulated by TORC2-Gad848. Collectively, our results reveal that Ryh1 positively controls the activation of the CIP via two distinct branches (Fig. 8). One involves proper trafficking and localization of key activators of the CIP, and is particularly relevant during MAPK activation in response to osmotic stress. The second branch is essential during cell wall damage or absence of glucose, and reinforces MAPK activation via TORC2-Gad8 to enhance Pck2 levels. In any case, this novel role of Ryh1 as elicitor of MAPK signaling might not be shared by budding yeast, since deletion of Ypt6 (Ryh1 ortholog) did not impair activation of MAPKs Slt2 and Hog1 in response to different stimuli (Suppl. Figure S7).

View Article: PubMed Central - PubMed

ABSTRACT

In eukaryotic cells, the highly conserved Target of Rapamycin (TOR) and the Mitogen Activated Protein Kinase (MAPK) signaling pathways elicit adaptive responses to extra- and intracellular conditions by regulating essential cellular functions. However, the nature of the functional relationships between both pathways is not fully understood. In the fission yeast Schizosaccharomyces pombe the cell integrity MAPK pathway (CIP) regulates morphogenesis, cell wall structure and ionic homeostasis. We show that the Rab GTPase Ryh1, a TORC2 complex activator, cross-activates the CIP and its core member, the MAPK Pmk1, by two distinct mechanisms. The first one involves TORC2 and its downstream effector, Akt ortholog Gad8, which together with TORC1 target Psk1 increase protein levels of the PKC ortholog Pck2 during cell wall stress or glucose starvation. Also, Ryh1 activates Pmk1 in a TORC2-independent fashion by prompting plasma membrane trafficking and stabilization of upstream activators of the MAPK cascade, including PDK ortholog Ksg1 or Rho1 GEF Rgf1. Besides, stress-activated Pmk1 cross-inhibits Ryh1 signaling by decreasing the GTPase activation cycle, and this ensures cell growth during alterations in phosphoinositide metabolism. Our results reveal a highly intricate cross-regulatory relationship between both pathways that warrants adequate cell adaptation and survival in response to environmental changes.

No MeSH data available.