Fine-Tuning of Platelet Responses by Serine/Threonine Protein Kinases and Phosphatases—Just the Beginning

2021 ◽  
Vol 41 (03) ◽  
pp. 206-216
Author(s):  
Yavar Shiravand ◽  
Ulrich Walter ◽  
Kerstin Jurk
Keyword(s):  
Protein Kinases ◽  
Mapk Signaling ◽  
Human Platelets ◽  
Fine Tuning ◽  
Contractile System ◽  
Crucial Component ◽  
Multiple Protein ◽  
Mitogen Activated Protein ◽  
Phosphatase 2A ◽  
Signaling Components

AbstractComprehensive proteomic analyses of human and murine platelets established an extraordinary intracellular repertoire of signaling components, which control crucial functions. The spectrum of platelet serine/threonine protein kinases (more than 100) includes the AGC family (protein kinase A, G, C [PKA, PKG, PKC]), the mitogen-activated protein kinases (MAPKs), and others. PKA and PKG have multiple significantly overlapping substrates in human platelets, which possibly affect functions with clear “signaling nodes” of regulation by multiple protein kinases/phosphatases. Signaling nodes are intracellular Ca2+ stores, the contractile system (myosin light chains), and other signaling components such as G-proteins, protein kinases, and protein phosphatases. An example for this fine-tuning is the tyrosine kinase Syk, a crucial component of platelet activation, which is controlled by several serine/threonine and tyrosine protein kinases as well as phosphatases. Other protein kinases including PKA/PKG modulate protein phosphatase 2A, which may be a master regulator of MAPK signaling in human platelets. Protein kinases and in particular MAPKs are targeted by an increasing number of clinically used inhibitors. However, the precise regulation and fine-tuning of these protein kinases and their effects on other signaling components in platelets are only superficially understood—just the beginning. However, promising future approaches are in sight.

scholarly journals Specific Functional Features of the Cell Integrity MAP Kinase Pathway in the Dimorphic Fission Yeast Schizosaccharomyces japonicus

2021 ◽  
Vol 7 (6) ◽  
pp. 482
Author(s):  
Elisa Gómez-Gil ◽  
Alejandro Franco ◽  
Beatriz Vázquez-Marín ◽  
Francisco Prieto-Ruiz ◽  
Armando Pérez-Díaz ◽  
...  
Keyword(s):  
Fission Yeast ◽  
Environmental Changes ◽  
Yeast Species ◽  
Mapk Signaling ◽  
Fine Tuning ◽  
Mitogen Activated Protein Kinase ◽  
Major Influence ◽  
Cell Integrity ◽  
Mitogen Activated Protein ◽  
Functional Features

Mitogen activated protein kinase (MAPK) signaling pathways execute essential functions in eukaryotic organisms by transducing extracellular stimuli into adaptive cellular responses. In the fission yeast model Schizosaccharomyces pombe the cell integrity pathway (CIP) and its core effector, MAPK Pmk1, play a key role during regulation of cell integrity, cytokinesis, and ionic homeostasis. Schizosaccharomyces japonicus, another fission yeast species, shows remarkable differences with respect to S. pombe, including a robust yeast to hyphae dimorphism in response to environmental changes. We show that the CIP MAPK module architecture and its upstream regulators, PKC orthologs Pck1 and Pck2, are conserved in both fission yeast species. However, some of S. pombe’s CIP-related functions, such as cytokinetic control and response to glucose availability, are regulated differently in S. japonicus. Moreover, Pck1 and Pck2 antagonistically regulate S. japonicus hyphal differentiation through fine-tuning of Pmk1 activity. Chimeric MAPK-swapping experiments revealed that S. japonicus Pmk1 is fully functional in S. pombe, whereas S. pombe Pmk1 shows a limited ability to execute CIP functions and promote S. japonicus mycelial development. Our findings also suggest that a modified N-lobe domain secondary structure within S. japonicus Pmk1 has a major influence on the CIP signaling features of this evolutionarily diverged fission yeast.

scholarly journals Comparative Analysis of Transmembrane Regulators of the Filamentous Growth Mitogen-Activated Protein Kinase Pathway Uncovers Functional and Regulatory Differences

2015 ◽  
Vol 14 (9) ◽  
pp. 868-883 ◽  
Author(s):  
Hema Adhikari ◽  
Lauren M. Caccamise ◽  
Tanaya Pande ◽  
Paul J. Cullen
Keyword(s):  
Protein Kinase ◽  
Mapk Pathway ◽  
Filamentous Growth ◽  
Mapk Signaling ◽  
Fine Tuning ◽  
Mitogen Activated Protein Kinase ◽  
Rate Limiting Step ◽  
Mitogen Activated Protein ◽  
Multiple Signaling ◽  
Growth Pathway

ABSTRACTFilamentous growth is a microbial differentiation response that involves the concerted action of multiple signaling pathways. In budding yeast, one pathway that regulates filamentous growth is a Cdc42p-dependent mitogen-activated protein kinase (MAPK) pathway. Several transmembrane (TM) proteins regulate the filamentous growth pathway, including the signaling mucin Msb2p, the tetraspan osmosensor Sho1p, and an adaptor Opy2p. The TM proteins were compared to identify common and unique features. Msb2p, Sho1p, and Opy2p associated by coimmunoprecipitation analysis but showed predominantly different localization patterns. The different localization patterns of the proteins resulted in part from different rates of turnover from the plasma membrane (PM). In particular, Msb2p (and Opy2p) were turned over rapidly compared to Sho1p. Msb2p signaled from the PM, and its turnover was a rate-limiting step in MAPK signaling. Genetic analysis identified unique phenotypes of cells overexpressing the TM proteins. Therefore, each TM regulator of the filamentous growth pathway has its own regulatory pattern and specific function in regulating filamentous growth. This specialization may be important for fine-tuning and potentially diversifying the filamentation response.

scholarly journals ERK1,2 Signalling Pathway along the Nephron and Its Role in Acid-base and Electrolytes Balance

2019 ◽  
Vol 20 (17) ◽  
pp. 4153 ◽  
Author(s):  
Giovanna Capolongo ◽  
Yoko Suzumoto ◽  
Mariavittoria D’Acierno ◽  
Mariadelina Simeoni ◽  
Giovambattista Capasso ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Mapk Signaling ◽  
Signalling Pathway ◽  
Renal Diseases ◽  
Cellular Functions ◽  
Acid Base ◽  
Mapk Activity ◽  
Extracellular Signal ◽  
Wide Range ◽  
Mitogen Activated Protein

Mitogen-activated protein kinases (MAPKs) are intracellular molecules regulating a wide range of cellular functions, including proliferation, differentiation, apoptosis, cytoskeleton remodeling and cytokine production. MAPK activity has been shown in normal kidney, and its over-activation has been demonstrated in several renal diseases. The extracellular signal-regulated protein kinases (ERK 1,2) signalling pathway is the first described MAPK signaling. Intensive investigations have demonstrated that it participates in the regulation of ureteric bud branching, a fundamental process in establishing final nephron number; in addition, it is also involved in the differentiation of the nephrogenic mesenchyme, indicating a key role in mammalian kidney embryonic development. In the present manuscript, we show that ERK1,2 signalling mediates several cellular functions also in mature kidney, describing its role along the nephron and demonstrating whether it contributes to the regulation of ion channels and transporters implicated in acid-base and electrolytes homeostasis.

scholarly journals Mos induces the in vitro activation of mitogen-activated protein kinases in lysates of frog oocytes and mammalian somatic cells.

1993 ◽  
Vol 4 (8) ◽  
pp. 781-790 ◽  
Author(s):  
E K Shibuya ◽  
J V Ruderman
Keyword(s):  
Protein Kinases ◽  
Somatic Cells ◽  
Mapk Signaling ◽  
Mapk Activation ◽  
Free System ◽  
Mitogen Activated Protein Kinases ◽  
Activation Pathway ◽  
In Vitro Activation ◽  
Mitogen Activated Protein

Mitogen-activated protein kinases (MAPKs) are rapidly and transiently activated when both quiescent Go-arrested cells and G2-arrested oocytes are stimulated to reenter the cell cycle. We previously developed a cell-free system from lysates of quiescent Xenopus oocytes that responds to oncogenic H-ras protein by activating a MAPK, p42MAPK. Here, we show that the oncogenic protein kinase mos is also a potent activator of p42MAPK in these lysates. Mos also induces p42MAPK activation in lysates of activated eggs taken at a time when neither mos nor p42MAPK is normally active, showing that the mos-responsive MAPK activation pathway persists beyond the stage where mos normally functions. Similarly, lysates of somatic cells (rabbit reticulocytes) also retain a mos-inducible MAPK activation pathway. The mos-induced activation of MAPKs in all three lysates leads to phosphorylation of the pp90rsk proteins, downstream targets of the MAPK signaling pathway in vivo. The in vitro activation of MAPKs by mos in cell-free systems derived from oocytes and somatic cells suggests that mos contributes to oncogenic transformation by inappropriately inducing the activation of MAPKs.

scholarly journals The Aspergillus fumigatus Phosphoproteome Reveals Roles of High-Osmolarity Glycerol Mitogen-Activated Protein Kinases in Promoting Cell Wall Damage and Caspofungin Tolerance

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Eliciane Cevolani Mattos ◽  
Lilian Pereira Silva ◽  
Clara Valero ◽  
Patrícia Alves de Castro ◽  
Thaila Fernanda dos Reis ◽  
...  
Keyword(s):  
Cell Wall ◽  
Aspergillus Fumigatus ◽  
Protein Kinases ◽  
Wall Stress ◽  
Mapk Signaling ◽  
Fungal Cell ◽  
Content Type ◽  
Cell Wall Stress ◽  
Cell Wall Damage ◽  
Mitogen Activated Protein

ABSTRACT The filamentous fungus Aspergillus fumigatus can cause a distinct set of clinical disorders in humans. Invasive aspergillosis (IA) is the most common life-threatening fungal disease of immunocompromised humans. The mitogen-activated protein kinase (MAPK) signaling pathways are essential to the adaptation to the human host. Fungal cell survival is highly dependent on the organization, composition, and function of the cell wall. Here, an evaluation of the global A. fumigatus phosphoproteome under cell wall stress caused by the cell wall-damaging agent Congo red (CR) revealed 485 proteins potentially involved in the cell wall damage response. Comparative phosphoproteome analyses with the ΔsakA, ΔmpkC, and ΔsakA ΔmpkC mutant strains from the osmotic stress MAPK cascades identify their additional roles during the cell wall stress response. Our phosphoproteomics allowed the identification of novel kinases and transcription factors (TFs) involved in osmotic stress and in the cell wall integrity (CWI) pathway. Our global phosphoproteome network analysis showed an enrichment for protein kinases, RNA recognition motif domains, and the MAPK signaling pathway. In contrast to the wild-type strain, there is an overall decrease of differentially phosphorylated kinases and phosphatases in ΔsakA, ΔmpkC, and ΔsakA ΔmpkC mutants. We constructed phosphomutants for the phosphorylation sites of several proteins differentially phosphorylated in the wild-type and mutant strains. For all the phosphomutants, there is an increase in the sensitivity to cell wall-damaging agents and a reduction in the MpkA phosphorylation upon CR stress, suggesting these phosphosites could be important for the MpkA modulation and CWI pathway regulation. IMPORTANCE Aspergillus fumigatus is an opportunistic human pathogen causing allergic reactions or systemic infections, such as invasive pulmonary aspergillosis in immunocompromised patients. The mitogen-activated protein kinase (MAPK) signaling pathways are essential for fungal adaptation to the human host. Fungal cell survival, fungicide tolerance, and virulence are highly dependent on the organization, composition, and function of the cell wall. Upon cell wall stress, MAPKs phosphorylate multiple target proteins involved in the remodeling of the cell wall. Here, we investigate the global phosphoproteome of the ΔsakA and ΔmpkC A. fumigatus and high-osmolarity glycerol (HOG) pathway MAPK mutants upon cell wall damage. This showed the involvement of the HOG pathway and identified novel protein kinases and transcription factors, which were confirmed by fungal genetics to be involved in promoting tolerance of cell wall damage. Our results provide understanding of how fungal signal transduction networks modulate the cell wall. This may also lead to the discovery of new fungicide drug targets to impact fungal cell wall function, fungicide tolerance, and virulence.

scholarly journals Sustained Incompatibility between MAPK Signaling and Pathogen Effectors

2020 ◽  
Vol 21 (21) ◽  
pp. 7954
Author(s):  
Julien Lang ◽  
Jean Colcombet
Keyword(s):  
Defense Responses ◽  
Mapk Signaling ◽  
Effector Proteins ◽  
Plant Defense Responses ◽  
Pathogen Effectors ◽  
Current State ◽  
Pathogen Effector ◽  
Mitogen Activated Protein ◽  
Effector Triggered Immunity ◽  
Signaling Components

In plants, Mitogen-Activated Protein Kinases (MAPKs) are important signaling components involved in developemental processes as well as in responses to biotic and abiotic stresses. In this review, we focus on the roles of MAPKs in Effector-Triggered Immunity (ETI), a specific layer of plant defense responses dependent on the recognition of pathogen effector proteins. Having inspected the literature, we synthesize the current state of knowledge concerning this topic. First, we describe how pathogen effectors can manipulate MAPK signaling to promote virulence, and how in parallel plants have developed mechanisms to protect themselves against these interferences. Then, we discuss the striking finding that the recognition of pathogen effectors can provoke a sustained activation of the MAPKs MPK3/6, extensively analyzing its implications in terms of regulation and functions. In line with this, we also address the question of how a durable activation of MAPKs might affect the scope of their substrates, and thereby mediate the emergence of possibly new ETI-specific responses. By highlighting the sometimes conflicting or missing data, our intention is to spur further research in order to both consolidate and expand our understanding of MAPK signaling in immunity.

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