scholarly journals Ancestral resurrection reveals evolutionary mechanisms of kinase plasticity

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Conor J Howard ◽  
Victor Hanson-Smith ◽  
Kristopher J Kennedy ◽  
Chad J Miller ◽  
Hua Jane Lou ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Evolutionary Divergence ◽  
Ancestral Reconstruction ◽  
Evolutionary Mechanisms ◽  
Cyclin Dependent Kinases ◽  
Mitogen Activated Protein ◽  
Kinase Specificity ◽  
Catalytic Cleft ◽  
Insight Into

Protein kinases have evolved diverse specificities to enable cellular information processing. To gain insight into the mechanisms underlying kinase diversification, we studied the CMGC protein kinases using ancestral reconstruction. Within this group, the cyclin dependent kinases (CDKs) and mitogen activated protein kinases (MAPKs) require proline at the +1 position of their substrates, while Ime2 prefers arginine. The resurrected common ancestor of CDKs, MAPKs, and Ime2 could phosphorylate substrates with +1 proline or arginine, with preference for proline. This specificity changed to a strong preference for +1 arginine in the lineage leading to Ime2 via an intermediate with equal specificity for proline and arginine. Mutant analysis revealed that a variable residue within the kinase catalytic cleft, DFGx, modulates +1 specificity. Expansion of Ime2 kinase specificity by mutation of this residue did not cause dominant deleterious effects in vivo. Tolerance of cells to new specificities likely enabled the evolutionary divergence of kinases.

scholarly journals Ancestral reconstruction reveals mechanisms of ERK regulatory evolution

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Dajun Sang ◽  
Sudarshan Pinglay ◽  
Rafal P Wiewiora ◽  
Myvizhi E Selvan ◽  
Hua Jane Lou ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Kinases ◽  
Human Cells ◽  
Ancestral State ◽  
Ancestral Reconstruction ◽  
Regulatory Evolution ◽  
Evolutionary Mechanisms ◽  
Kinase Specificity ◽  
Shed Light

Protein kinases are crucial to coordinate cellular decisions and therefore their activities are strictly regulated. Previously we used ancestral reconstruction to determine how CMGC group kinase specificity evolved (Howard et al., 2014). In the present study, we reconstructed ancestral kinases to study the evolution of regulation, from the inferred ancestor of CDKs and MAPKs, to modern ERKs. Kinases switched from high to low autophosphorylation activity at the transition to the inferred ancestor of ERKs 1 and 2. Two synergistic amino acid changes were sufficient to induce this change: shortening of the β3-αC loop and mutation of the gatekeeper residue. Restoring these two mutations to their inferred ancestral state led to a loss of dependence of modern ERKs 1 and 2 on the upstream activating kinase MEK in human cells. Our results shed light on the evolutionary mechanisms that led to the tight regulation of a kinase that is central in development and disease.

scholarly journals The Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinases MK2 and MK3 Cooperate in Stimulation of Tumor Necrosis Factor Biosynthesis and Stabilization of p38 MAPK

2006 ◽  
Vol 27 (1) ◽  
pp. 170-181 ◽  
Author(s):  
N. Ronkina ◽  
A. Kotlyarov ◽  
O. Dittrich-Breiholz ◽  
M. Kracht ◽  
E. Hitti ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tumor Necrosis Factor ◽  
Protein Kinases ◽  
Tumor Necrosis ◽  
Mitogen Activated Protein Kinase ◽  
Double Knockout ◽  
Mitogen Activated Protein ◽  
Deficient Mice ◽  
Necrosis Factor

ABSTRACT MK2 and MK3 represent protein kinases downstream of p38 mitogen-activated protein kinase (MAPK). Deletion of the MK2 gene in mice resulted in an impaired inflammatory response although MK3, which displays extensive structural similarities and identical functional properties in vitro, is still present. Here, we analyze tumor necrosis factor (TNF) production and expression of p38 MAPK and tristetraprolin (TTP) in MK3-deficient mice and demonstrate that there are no significant differences with wild-type animals. We show that in vivo MK2 and MK3 are expressed and activated in parallel. However, the level of activity of MK2 is always significantly higher than that of MK3. Accordingly, we hypothesized that MK3 could have significant effects only in an MK2-free background and generated MK2/MK3 double-knockout mice. Unexpectedly, these mice are viable and show no obvious defects due to loss of compensation between MK2 and MK3. However, there is a further reduction of TNF production and expression of p38 and TTP in double-knockout mice compared to MK2-deficient mice. This finding, together with the observation that ectopically expressed MK3 can rescue MK2 deficiency similarly to MK2, indicates that both kinases share the same physiological function in vivo but are expressed to different levels.

scholarly journals The MKK7 Gene Encodes a Group of c-Jun NH2-Terminal Kinase Kinases

1999 ◽  
Vol 19 (2) ◽  
pp. 1569-1581 ◽  
Author(s):  
Cathy Tournier ◽  
Alan J. Whitmarsh ◽  
Julie Cavanagh ◽  
Tamera Barrett ◽  
Roger J. Davis
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Cultured Cells ◽  
Biochemical Properties ◽  
Mitogen Activated Protein Kinase ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Extracellular Stimuli ◽  
Jnk Activation

ABSTRACT The c-Jun NH2-terminal protein kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) group and is an essential component of a signaling cascade that is activated by exposure of cells to environmental stress. JNK activation is regulated by phosphorylation on both Thr and Tyr residues by a dual-specificity MAPK kinase (MAPKK). Two MAPKKs, MKK4 and MKK7, have been identified as JNK activators. Genetic studies demonstrate that MKK4 and MKK7 serve nonredundant functions as activators of JNK in vivo. We report here the molecular cloning of the gene that encodes MKK7 and demonstrate that six isoforms are created by alternative splicing to generate a group of protein kinases with three different NH2 termini (α, β, and γ isoforms) and two different COOH termini (1 and 2 isoforms). The MKK7α isoforms lack an NH2-terminal extension that is present in the other MKK7 isoforms. This NH2-terminal extension binds directly to the MKK7 substrate JNK. Comparison of the activities of the MKK7 isoforms demonstrates that the MKK7α isoforms exhibit lower activity, but a higher level of inducible fold activation, than the corresponding MKK7β and MKK7γ isoforms. Immunofluorescence analysis demonstrates that these MKK7 isoforms are detected in both cytoplasmic and nuclear compartments of cultured cells. The presence of MKK7 in the nucleus was not, however, required for JNK activation in vivo. These data establish that theMKK4 and MKK7 genes encode a group of protein kinases with different biochemical properties that mediate activation of JNK in response to extracellular stimuli.

scholarly journals Dynamics of Dual Specificity Phosphatases and Their Interplay with Protein Kinases in Immune Signaling

2019 ◽  
Vol 20 (9) ◽  
pp. 2086 ◽  
Author(s):  
Yashwanth Subbannayya ◽  
Sneha M. Pinto ◽  
Korbinian Bösl ◽  
T. S. Keshava Prasad ◽  
Richard K. Kandasamy
Keyword(s):  
Immune Response ◽  
Protein Kinases ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Tlr4 Signaling ◽  
Cyclin Dependent Kinases ◽  
Therapeutic Modalities ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Dual Specificity Phosphatases

Dual specificity phosphatases (DUSPs) have a well-known role as regulators of the immune response through the modulation of mitogen-activated protein kinases (MAPKs). Yet the precise interplay between the various members of the DUSP family with protein kinases is not well understood. Recent multi-omics studies characterizing the transcriptomes and proteomes of immune cells have provided snapshots of molecular mechanisms underlying innate immune response in unprecedented detail. In this study, we focus on deciphering the interplay between members of the DUSP family with protein kinases in immune cells using publicly available omics datasets. Our analysis resulted in the identification of potential DUSP-mediated hub proteins including MAPK7, MAPK8, AURKA, and IGF1R. Furthermore, we analyzed the association of DUSP expression with TLR4 signaling and identified VEGF, FGFR, and SCF-KIT pathway modules to be regulated by the activation of TLR4 signaling. Finally, we identified several important kinases including LRRK2, MAPK8, and cyclin-dependent kinases as potential DUSP-mediated hubs in TLR4 signaling. The findings from this study have the potential to aid in the understanding of DUSP signaling in the context of innate immunity. Further, this will promote the development of therapeutic modalities for disorders with aberrant DUSP signaling.

scholarly journals Dusp-5 and Snrk-1 coordinately function during vascular development and disease

Blood ◽  
2009 ◽  
Vol 113 (5) ◽  
pp. 1184-1191 ◽  
Author(s):  
Kallal Pramanik ◽  
Chang Zoon Chun ◽  
Maija K. Garnaas ◽  
Ganesh V. Samant ◽  
Keguo Li ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Vascular Development ◽  
Serine Threonine Kinase ◽  
Lateral Plate ◽  
Mitogen Activated Protein Kinases ◽  
Cellular Processes ◽  
Mitogen Activated Protein ◽  
Integral Role ◽  
Dual Specific Phosphatase

Abstract Mitogen-activated protein kinases play an integral role in several cellular processes. To regulate mitogen-activated protein kinases, cells express members of a counteracting group of proteins called phosphatases. In this study, we have identified a specific role that one member of this family of phosphatases, dual-specific phosphatase-5 (Dusp-5) plays in vascular development in vivo. We have determined that dusp-5 is expressed in angioblasts and in established vasculature and that it counteracts the function of a serine threonine kinase, Snrk-1, which also plays a functional role in angioblast development. Together, Dusp-5 and Snrk-1 control angioblast populations in the lateral plate mesoderm with Dusp-5 functioning downstream of Snrk-1. Importantly, mutations in dusp-5 and snrk-1 have been identified in affected tissues of patients with vascular anomalies, implicating the Snrk-1–Dusp-5 signaling pathway in human disease.

scholarly journals p38β Mitogen-Activated Protein Kinase Modulates Its Own Basal Activity by Autophosphorylation of the Activating Residue Thr180 and the Inhibitory Residues Thr241 and Ser261

2016 ◽  
Vol 36 (10) ◽  
pp. 1540-1554 ◽  
Author(s):  
Jonah Beenstock ◽  
Dganit Melamed ◽  
Navit Mooshayef ◽  
Dafna Mordechay ◽  
Benjamin P. Garfinkel ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Protein Kinases ◽  
Mitogen Activated Protein Kinase ◽  
Activation Loop ◽  
Structural Element ◽  
Muscle Tissues ◽  
Mitogen Activated Protein ◽  
Loop Residue ◽  
Mapk Kinases

Many enzymes are self-regulated and can either inhibit or enhance their own catalytic activity. Enzymes that do both are extremely rare. Many protein kinases autoactivate by autophosphorylating specific sites at their activation loop and are inactivated by phosphatases. Although mitogen-activated protein kinases (MAPKs) are usually activated by dual phosphorylation catalyzed by MAPK kinases (MAPKKs), the MAPK p38β is exceptional and is capable of self-activation bycisautophosphorylation of its activation loop residue T180. We discovered that p38β also autophosphorylates intranstwo previously unknown sites residing within a MAPK-specific structural element known as the MAPK insert: T241 and S261. Whereas phosphorylation of T180 evokes catalytic activity, phosphorylation of S261 reduces the activity of T180-phosphorylated p38β, and phosphorylation of T241 reduces its autophosphorylation intrans. Both phosphorylations do not affect the activity of dually phosphorylated p38β. T241 of p38β is found phosphorylatedin vivoin bone and muscle tissues. In myogenic cell lines, phosphorylation of p38β residue T241 is correlated with differentiation to myotubes. T241 and S261 are also autophosphorylated in intrinsically active variants of p38α, but in this protein, they probably play a different role. We conclude that p38β is an unusual enzyme that automodulates its basal, MAPKK-independent activity by several autophosphorylation events, which enhance and suppress its catalytic activity.

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