In the Beginning, There Was Protein Phosphorylation

Abstract

The importance of reversible protein phosphorylation to cellular regulation cannot be overstated. In eukaryotic cells, protein kinase/phosphatase signaling pathways regulate a staggering number of cellular processes, including cell proliferation, cell death (apoptosis, necroptosis, necrosis), metabolism (at both the cellular and organismal levels), behavior and neurological function, development, and pathogen resistance. Although protein phosphorylation as a mode of eukaryotic cell regulation is familiar to most biochemists, many are less familiar with protein kinase/phosphatase signaling networks that function in prokaryotes. In this thematic minireview series, we present four minireviews that cover the important field of prokaryotic protein phosphorylation.The phenomenon of reversible protein phosphorylation was discovered Ͼ50 years ago by Edwin Krebs and Edmond Fischer and described in a series of classic papers published in this journal. These papers described a protein kinase activity that converted phosphorylase b to phosphorylase a and laid the groundwork for dissecting the molecular signaling pathway by which epinephrine could inactivate muscle glycogen synthase (1, 2).The notion of a multistep protein kinase pathway triggered by the production of second messengers and inactivated by protein phosphatases also set a paradigm for understanding signal transduction by protein phosphorylation cascades. Numerous protein kinase cascades have been described in the intervening years, including the MAPKs, the Akt and mTOR pathways, the NF-B pathway, the JAK/STAT pathway, and others. Each of these pathways is recruited by extracellular stimuli acting through receptors that transduce these signals through the generation of second messengers (cyclic nucleotides, inositol phosphates, etc.), receptor Tyr kinase autophosphorylation (a form of second messenger in which such phosphorylation, at the receptor intracellular extensions, prompts the binding and membrane recruitment of downstream adaptors), or the more recently discovered stimulus-induced formation of second messengers consisting of free Lys 63 -linked polyubiquitin chains (3-9).Eukaryotic protein kinases fall into three broad classes: Ser/ Thr-specific protein kinases that phosphorylate Ser or Thr residues exclusively, Tyr kinases that phosphorylate Tyr exclusively, or dual-specificity kinases (exemplified by MEKs) that can phosphorylate Tyr and Ser/Thr concomitantly (10,

Comparative proteomic analysis of Xanthomonas citri ssp. citri periplasmic proteins reveals changes in cellular envelope metabolism during in vitro pathogenicity induction

“…Evidence for phosphorylation of the 60‐kDa chaperonin has been reported for mycobacterial GroEL (Kumar et al ., ), but there are no reports for XAC. Phosphorylation events in Xcc have been reported (Musa et al ., ), together with the participation of prokaryote kinases in host–pathogen interactions involving other bacterial species (Kyriakis, ). In addition to GAPDH and 60‐kDa chaperonin, transglycosylase was also detected in this study in several spots in XAM‐M (Table , Fig.…”

Plasmonic ruler on field-effect devices for kinase drug discovery applications

“…Kinase mediated phosphorylation is one of the major post translational modifications of the proteins essential for the regulation of various cellular functions, such as cell cycle, motility, metabolism or genetic expression (Cohen 2002;Noble et al 2004;Overington et al 2006;Weller 1979). Abnormal phosphorylation of proteins is associated with etiology of fatal diseases such as cancer (Chakraborty et al 2014;Viatour et al 2005), cardiovascular (Honda et al 1998;Liu and Molkentin 2011), spinal (de Laat et al 2014;Kyriakis 2014) and neural disorders (Abeliovich 2014;Buee et al 2000). In this perspective the development of inhibitors for kinases could serve as powerful drugs for a specific disease associated with phosphorylation.…”

Integrative and quantitative view of the CtrA regulatory network in a stalked budding bacterium

“…To ensure the correct timing of events, cells need to sense multiple input signals and integrate these signals in order to determine whether or not to start a certain process. A common strategy in both eukaryotes and prokaryotes is to use protein phosphorylation as a switching mechanism in this cellular information switchboard [1][2][3]. The integration of different signals often involves complex phosphorylation cascades, in which the reception of a signal leads to the phosphorylation of proteins, which then in turn phosphorylate downstream targets.…”