Asynchronous Pattern of MAPKs' Activity during Aging of Different Tissues and of Distinct Types of Skeletal Muscle.

The MAPK p38α was proposed to be a prominent promoter of skeletal muscle aging. The skeletal muscle tissue is composed of various muscle types, and it is not known if p38α is associated with aging in all of them. It is also not known if p38α is associated with aging of other tissues.

The ER-Golgi transport of influenza virus through NS1-Sec13 association during virus replication.

Influenza A virus is a respiratory virus that can cause complications such as acute bronchitis and secondary bacterial pneumonia. Drug therapies and vaccines are available against influenza, albeit limited by drug resistance and the non-universal vaccine administration. Hence there is a need for host-targeted therapies against influenza to provide an effective alternative therapeutic target.

Differential Modulation of the Phosphoproteome by the MAP Kinases Isoforms p38α and p38β.

The p38 members of the mitogen-activated protein kinases (MAPKs) family mediate various cellular responses to stress conditions, inflammatory signals, and differentiation factors. They are constitutively active in chronic inflammatory diseases and some cancers. The differences between their transient effects in response to signals and the chronic effect in diseases are not known.

A conserved arginine within the αC-helix of Erk1/2 is a latch of autoactivation and of oncogenic capabilities.

Eukaryotic protein kinases (EPKs) adopt an active conformation following phosphorylation of a particular activation loop residue. Most EPKs spontaneously autophosphorylate this residue. While structure-function relationships of the active conformation are essentially understood, those of the "prone-to-autophosphorylate" conformation are unclear.

A Review and Meta-Analysis of Influenza Interactome Studies.

Annually, the influenza virus causes 500,000 deaths worldwide. Influenza-associated mortality and morbidity is especially high among the elderly, children, and patients with chronic diseases. While there are antivirals available against influenza, such as neuraminidase inhibitors and adamantanes, there is growing resistance against these drugs.

Targeting the p38α pathway in chronic inflammatory diseases: Could activation, not inhibition, be the appropriate therapeutic strategy?

Chronic inflammatory diseases (CIDs) afflict millions worldwide and remain incurable. The mitogen-activated protein kinase (MAPK) p38α is a critical node in the intricate acute inflammatory response. It induces the production of various pro-inflammatory mediators, primarily via the MAPK-activated protein kinase 2 (MK2).

Active p38α causes macrovesicular fatty liver in mice.

One third of the western population suffers from nonalcoholic fatty liver disease (NAFLD), which may ultimately develop into hepatocellular carcinoma (HCC). The molecular event(s) that triggers the disease are not clear. Current understanding, known as the multiple hits model, suggests that NAFLD is a result of diverse events at several tissues (e.

Expression of a constitutively active p38α mutant in mice causes early death, anemia, and accumulation of immunosuppressive cells.

The MAP kinase p38α is associated with numerous processes in eukaryotes, and its elevated activity is a prominent feature of inflammatory diseases, allergies, and aging. Since p38α is a nodal component of a complex signaling network, it is difficult to reveal exactly how p38α contributes to disparate outcomes. Identification of p38α -specific effects requires activation of p38α per se in vivo.

Hog1-induced transcription of RTC3 and HSP12 is robust and occurs in cells lacking Msn2, Msn4, Hot1 and Sko1.

The yeast MAP kinase Hog1 pathway activates transcription of several hundreds genes. Large-scale gene expression and DNA binding assays suggest that most Hog1-induced genes are regulated by the transcriptional activators Msn2/4, Hot1 and Sko1. These studies also revealed the target genes of each activator and the putative binding sites on their promoters.

Mutations That Confer Drug-Resistance, Oncogenicity and Intrinsic Activity on the ERK MAP Kinases-Current State of the Art.

Unique characteristics distinguish extracellular signal-regulated kinases (Erks) from other eukaryotic protein kinases (ePKs). Unlike most ePKs, Erks do not autoactivate and they manifest no basal activity; they become catalysts only when dually phosphorylated on neighboring Thr and Tyr residues and they possess unique structural motifs. Erks function as the sole targets of the receptor tyrosine kinases (RTKs)-Ras-Raf-MEK signaling cascade, which controls numerous physiological processes and is mutated in most cancers.

An Activating Mutation in ERK Causes Hyperplastic Tumors in a Mutant Tissue in .

Receptor tyrosine kinase signaling plays prominent roles in tumorigenesis, and activating oncogenic point mutations in the core pathway components Ras, Raf, or MEK are prevalent in many types of cancer. Intriguingly, however, analogous oncogenic mutations in the downstream effector kinase ERK have not been described or validated To determine if a point mutation could render ERK intrinsically active and oncogenic, we have assayed in the effects of a mutation that confers constitutive activity upon a yeast ERK ortholog and has also been identified in a few human tumors. Our analyses indicate that a fly ERK ortholog harboring this mutation alone (Rolled), and more so in conjunction with the known mutation (Rolled), suppresses multiple phenotypes caused by loss of Ras-Raf-MEK pathway activity, consistent with an intrinsic activity that is independent of upstream signaling.

Alternative Experimental Models for Studying Influenza Proteins, Host-Virus Interactions and Anti-Influenza Drugs.

Ninety years after the discovery of the virus causing the influenza disease, this malady remains one of the biggest public health threats to mankind. Currently available drugs and vaccines only partially reduce deaths and hospitalizations. Some of the reasons for this disturbing situation stem from the sophistication of the viral machinery, but another reason is the lack of a complete understanding of the molecular and physiological basis of viral infections and host-pathogen interactions.

Isolation and Characterization of Intrinsically Active (MEK-Independent) Mutants of Mpk1/Erk.

The extracellular-regulated kinase (Erk) pathway is a major determinant in the control of diverse cellular processes, such as proliferation, differentiation, survival, and motility. The pathway executes its effects through kinases of the Erk family. Erks are not only critical for a variety of physiological processes, but are also associated with neurodegenerative diseases, cardiovascular diseases, diabetes and a large number of human cancers.

How Do Protein Kinases Take a Selfie (Autophosphorylate)?

Eukaryotic protein kinases (EPKs) control most biological processes and play central roles in many human diseases. To become catalytically active, EPKs undergo conversion from an inactive to an active conformation, an event that depends upon phosphorylation of their activation loop. Intriguingly, EPKs can use their own catalytic activity to achieve this critical phosphorylation.

Variants of the yeast MAPK Mpk1 are fully functional independently of activation loop phosphorylation.

MAP kinases of the ERK family are conserved from yeast to humans. Their catalytic activity is dependent on dual phosphorylation of their activation loop's TEY motif, catalyzed by MAPK kinases (MEKs). Here we studied variants of Mpk1, a yeast orthologue of Erk, which is essential for cell wall integrity.

Tighter αC-helix-αL16-helix interactions seem to make p38α less prone to activation by autophosphorylation than Hog1.

Many eukaryotic protein kinases (EPKs) are autoactivated through autophosphorylation of their activation loop. Mitogen-activated protein (MAP) kinases do not autophosphorylate spontaneously; relying instead upon mitogen-activated protein kinase (MAPK) kinases (MKKs) for their activation loop phosphorylation. Yet, in previous studies we identified mutations in the yeast MAPK high osmolarity glycerol (Hog1) that render it capable of spontaneous autophosphorylation and consequently intrinsically active (MKK-independent).

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

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.

Intrinsically active variants of Erk oncogenically transform cells and disclose unexpected autophosphorylation capability that is independent of TEY phosphorylation.

The receptor-tyrosine kinase (RTK)/Ras/Raf pathway is an essential cascade for mediating growth factor signaling. It is abnormally overactive in almost all human cancers. The downstream targets of the pathway are members of the extracellular regulated kinases (Erk1/2) family, suggesting that this family is a mediator of the oncogenic capability of the cascade.

The yeast Hot1 transcription factor is critical for activating a single target gene, STL1.

Transcription factors are commonly activated by signal transduction cascades and induce expression of many genes. They therefore play critical roles in determining the cell's fate. The yeast Hog1 MAP kinase pathway is believed to control the transcription of hundreds of genes via several transcription factors.

Transmembrane signaling in Saccharomyces cerevisiae as a model for signaling in metazoans: state of the art after 25 years.

In the very first article that appeared in Cellular Signalling, published in its inaugural issue in October 1989, we reviewed signal transduction pathways in Saccharomyces cerevisiae. Although this yeast was already a powerful model organism for the study of cellular processes, it was not yet a valuable instrument for the investigation of signaling cascades. In 1989, therefore, we discussed only two pathways, the Ras/cAMP and the mating (Fus3) signaling cascades.

The p38β mitogen-activated protein kinase possesses an intrinsic autophosphorylation activity, generated by a short region composed of the α-G helix and MAPK insert.

Protein kinases are regulated by a large number of mechanisms that vary from one kinase to another. However, a fundamental activation mechanism shared by all protein kinases is phosphorylation of a conserved activation loop threonine residue. This is achieved in many cases via autophosphorylation.

DEF pocket in p38α facilitates substrate selectivity and mediates autophosphorylation.

Signaling processes are primarily promoted by molecular recognition and corresponding protein-protein interactions. One of the key eukaryotic signaling pathways is the MAP kinase cascade involved in vital cellular processes such as cell proliferation, differentiation, apoptosis, and stress response. The principle recognition site of MAP kinases, the common docking (CD) region, forms selective interactions with substrates, upstream activators, and phosphatases.

Osmostress induces autophosphorylation of Hog1 via a C-terminal regulatory region that is conserved in p38α.

Many protein kinases require phosphorylation at their activation loop for induction of catalysis. Mitogen-activated protein kinases (MAPKs) are activated by a unique mode of phosphorylation, on neighboring Tyrosine and Threonine residues. Whereas many kinases obtain their activation via autophosphorylation, MAPKs are usually phosphorylated by specific, dedicated, MAPK kinases (MAP2Ks).

Turbidostat culture of Saccharomyces cerevisiae W303-1A under selective pressure elicited by ethanol selects for mutations in SSD1 and UTH1.

We investigated the genetic causes of ethanol tolerance by characterizing mutations selected in Saccharomyces cerevisiae W303-1A under the selective pressure of ethanol. W303-1A was subjected to three rounds of turbidostat, in a medium supplemented with increasing amounts of ethanol. By the end of selection, the growth rate of the culture has increased from 0.