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1. Pseudophosphatases as Regulators of MAPK Signaling

   https://doi.org/10.3390/ijms222212595  

   Hepworth, Emma Marie; Hinton, Shantá D. (November 2021, International Journal of Molecular Sciences)

   Mitogen-activated protein kinase (MAPK) signaling pathways are highly conserved regulators of eukaryotic cell function. These enzymes regulate many biological processes, including the cell cycle, apoptosis, differentiation, protein biosynthesis, and oncogenesis; therefore, tight control of the activity of MAPK is critical. Kinases and phosphatases are well established as MAPK activators and inhibitors, respectively. Kinases phosphorylate MAPKs, initiating and controlling the amplitude of the activation. In contrast, MAPK phosphatases (MKPs) dephosphorylate MAPKs, downregulating and controlling the duration of the signal. In addition, within the past decade, pseudoenzymes of these two families, pseudokinases and pseudophosphatases, have emerged as bona fide signaling regulators. This review discusses the role of pseudophosphatases in MAPK signaling, highlighting the function of phosphoserine/threonine/tyrosine-interacting protein (STYX) and TAK1-binding protein (TAB 1) in regulating MAPKs. Finally, a new paradigm is considered for this well-studied cellular pathway, and signal transduction pathways in general. 

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2. Not your Mother’s MAPKs: Apicomplexan MAPK function in daughter cell budding

   https://doi.org/10.1371/journal.ppat.1010849  

   O’Shaughnessy, William J.; Dewangan, Pravin S.; Paiz, E. Ariana; Reese, Michael L. (October 2022, PLOS Pathogens)

   Kafsack, Bjorn F.C. (Ed.)

   Reversible phosphorylation by protein kinases is one of the core mechanisms by which biological signals are propagated and processed. Mitogen-activated protein kinases, or MAPKs, are conserved throughout eukaryotes where they regulate cell cycle, development, and stress response. Here, we review advances in our understanding of the function and biochemistry of MAPK signaling in apicomplexan parasites. As expected for well-conserved signaling modules, MAPKs have been found to have multiple essential roles regulating both Toxoplasma tachyzoite replication and sexual differentiation in Plasmodium . However, apicomplexan MAPK signaling is notable for the lack of the canonical kinase cascade that normally regulates the networks, and therefore must be regulated by a distinct mechanism. We highlight what few regulatory relationships have been established to date, and discuss the challenges to the field in elucidating the complete MAPK signaling networks in these parasites. 

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3. Combinatorial phosphorylation modulates the structure and function of the G protein gamma subunit in yeast

   https://doi.org/https://doi.org/10.1101/2020.06.09.143123  

   Toosi, Zahra; Su, Xinya; Choudhury, Shilpa; Li, Wei; Pang, Yui Tik; Gumbart, James C; Torres, Matthew P (January 2020, NA)

   Protein intrinsically disordered regions (IDRs) are often targets of combinatorial post-translational modifications (PTMs) that serve to regulate protein structure and/or function. Emerging evidence suggests that the N-terminal tails of G protein γ subunits – essential components of heterotrimeric G protein complexes – are intrinsically disordered, highly phosphorylated governors of G protein signaling. Here, we demonstrate that the yeast Gγ Ste18 undergoes combinatorial, multi-site phosphorylation within its N-terminal IDR. Phosphorylation at S7 is responsive to GPCR activation and osmotic stress while phosphorylation at S3 is responsive to glucose stress and is a quantitative indicator of intracellular pH. Each site is phosphorylated by a distinct set of kinases and both are also interactive, such that phosphomimicry at one site affects phosphorylation on the other. Lastly, we show that phosphorylation produces subtle yet clear changes in IDR structure and that different combinations of phosphorylation modulate the activation rate and amplitude of the scaffolded MAPK Fus3. These data place Gγ subunits among the growing list of intrinsically disordered proteins that exploit combinatorial post-translational modification to govern signaling pathway output. 

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4. From growth to stress: RAF-like kinases as integrators of hormonal signals in plants

   https://doi.org/10.1093/jxb/eraf086  

   Park, Hye_Lin; Yoon, Gyeong_Mee; McSteen, ed., Paula (March 2025, Journal of Experimental Botany)

   Abstract RAF-like kinases, members of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, are central integrators of external and internal signals in plant stress responses and growth regulation. These kinases mediate signaling through multiple hormone pathways, including abscisic acid-dependent and -independent pathways, ethylene signaling, and rapid auxin responses. Unlike typical MAPKKKs that function through kinase cascades, RAF-like kinases primarily employ direct phosphorylation of downstream targets and dynamic subcellular localization to mediate specific physiological responses. Here, we review the emerging roles of RAF-like kinases in Arabidopsis thaliana, highlighting their integrative functions in hormone signaling, stress responses, and growth control. The complex interplay between different RAF-like kinase subgroups and their diverse cellular targets underscores the intricate regulatory mechanisms plants have evolved to coordinate environmental responses with development. 

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5. The Importance of Protein Phosphorylation for Signaling and Metabolism in Response to Diel Light Cycling and Nutrient Availability in a Marine Diatom

   https://doi.org/10.3390/biology9070155  

   Tan, Maxine H.; Smith, Sarah R.; Hixson, Kim K.; Tan, Justin; McCarthy, James K.; Kustka, Adam B.; Allen, Andrew E. (July 2020, Biology)

   null (Ed.)

   Diatoms are major contributors to global primary production and their populations in the modern oceans are affected by availability of iron, nitrogen, phosphate, silica, and other trace metals, vitamins, and infochemicals. However, little is known about the role of phosphorylation in diatoms and its role in regulation and signaling. We report a total of 2759 phosphorylation sites on 1502 proteins detected in Phaeodactylum tricornutum. Conditionally phosphorylated peptides were detected at low iron (n = 108), during the diel cycle (n = 149), and due to nitrogen availability (n = 137). Through a multi-omic comparison of transcript, protein, phosphorylation, and protein homology, we identify numerous proteins and key cellular processes that are likely under control of phospho-regulation. We show that phosphorylation regulates: (1) carbon retrenchment and reallocation during growth under low iron, (2) carbon flux towards lipid biosynthesis after the lights turn on, (3) coordination of transcription and translation over the diel cycle and (4) in response to nitrogen depletion. We also uncover phosphorylation sites for proteins that play major roles in diatom Fe sensing and utilization, including flavodoxin and phytotransferrin (ISIP2A), as well as identify phospho-regulated stress proteins and kinases. These findings provide much needed insight into the roles of protein phosphorylation in diel cycling and nutrient sensing in diatoms. 

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