LmxMPK4, an essential mitogen-activated protein kinase of Leishmania mexicana is phosphorylated and activated by the STE7-like protein kinase LmxMKK5

Freyend, Simona John von; Rosenqvist, Heidi; Fink, Annette; Melzer, Inga Maria; Clos, Joachim; Jensen, Ole N.; Wiese, Martin

doi:10.1016/j.ijpara.2010.02.004

Cited by 23 publications

(23 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As expected from the role of MPK3 in regulating flagellar length, MKK1 knockouts also have a shortened flagellum. The second pair, as demonstrated by in vitro studies, is comprised of LmxMPK4 and its activator MKK5 (von Freyend et al, 2010). LmxMPK4 has been proposed as a potential drug target.…”

Section: Introductionmentioning

confidence: 99%

Trypanosoma brucei: Two mitogen activated protein kinase kinases are dispensable for growth and virulence of the bloodstream form

Jensen

Kifer

Parsons

2011

Experimental Parasitology

View full text Add to dashboard Cite

Mitogen activated protein kinase cascades function in eukaryotic responses to the environment and stress. Trypanosomatid parasites possess protein kinases with sequences characteristic of kinases in such cascades. In this report we use gene knockouts to demonstrate that two mitogen activated kinase kinase genes, MKK1 (Tb927.3.4860) and MKK5 (Tb927.10.5270), are not essential in the pathogenic bloodstream stage of Trypanosoma brucei, either in vitro or in vivo. Bloodstream forms lacking MKK1 showed decreased growth at 39°C as compared to the parental line. However, unlike its Leishmania orthologue, T. brucei MKK1 does not appear to play a significant role in flagellar biogenesis.

show abstract

Section: Introductionmentioning

confidence: 99%

Trypanosoma brucei: Two mitogen activated protein kinase kinases are dispensable for growth and virulence of the bloodstream form

Jensen

Kifer

Parsons

2011

Experimental Parasitology

View full text Add to dashboard Cite

show abstract

“…Ashutosh and coworkers recently reported the specific activity of recombinant MAPK1 from Leishmania donovani to be 11.66 nmol ATP consumed/min/mg protein [43]. Likewise, new kinases aligning with kinases upstream in the MAPK signaling pathway from Apocomplexans ( T. annulata ) [49], Kinetoplastids ( T. brucei ) [Swinney DC, unpublished results] and Leishmania mexicana [50] and Schistosoma mansoni [51] can accept MBP as a protein substrate.…”

Section: Generic Substratesmentioning

confidence: 99%

Enzyme Activity Assays for Protein Kinases: Strategies to Identify Active Substrates

Haubrich

Swinney²

2016

CDDT

View full text Add to dashboard Cite

Protein kinases are an important class of enzymes and drug targets. New opportunities to discover medicines for neglected diseases can be leveraged by the extensive kinase tools and knowledge created in targeting human kinases. A valuable tool for kinase drug discovery is an enzyme assay that measures catalytic function. The functional assay can be used to identify inhibitors, estimate affinity, characterize molecular mechanisms of action (MMOAs) and evaluate selectivity. However, establishing an enzyme assay for a new kinases requires identification of a suitable substrate. Identification of a new kinase’s endogenous physiologic substrate and function can be extremely costly and time consuming. Fortunately, most kinases are promiscuous and will catalyze the phosphotransfer from ATP to alternative substrates with differing degrees of catalytic efficiency. In this manuscript we review strategies and successes in the identification of alternative substrates for kinases from organisms responsible for many of the neglected tropical diseases (NTDs) towards the goal of informing strategies to identify substrates for new kinases. Approaches for establishing a functional kinase assay include measuring auto-activation and use of generic substrates and peptides. The most commonly used generic substrates are casein, myelin basic protein, and histone. Sequence homology modeling can provide insights into the potential substrates and the requirement for activation. Empirical approaches that can identify substrates include screening of lysates (which may also help identify native substrates) and use of peptide arrays. All of these approaches have been used with a varying degree of success to identify alternative substrates.

show abstract

“…mexicana , required for its activation. This effort is the basis for the development of drug screening assays of Lmx MPK4 (John von Freyend et al 2010 ).…”

Section: Kinasesmentioning

confidence: 99%

Selection of Molecular Targets for Drug Development Against Trypanosomatids

Smirlis

Soares

2013

Subcellular Biochemistry

View full text Add to dashboard Cite

Trypanosomatid parasites are a group of flagellated protozoa that includes the genera Leishmania and Trypanosoma, which are the causative agents of diseases (leishmaniases, sleeping sickness and Chagas disease) that cause considerable morbidity and mortality, affecting more than 27 million people worldwide. Today no effective vaccines for the prevention of these diseases exist, whereas current chemotherapy is ineffective, mainly due to toxic side effects of current drugs and to the emergence of drug resistance and lack of cost effectiveness. For these reasons, rational drug design and the search of good candidate drug targets is of prime importance. The search for drug targets requires a multidisciplinary approach. To this end, the completion of the genome project of many trypanosomatid species gives a vast amount of new information that can be exploited for the identification of good drug candidates with a prediction of "druggability" and divergence from mammalian host proteins. In addition, an important aspect in the search for good drug targets is the "target identification" and evaluation in a biological pathway, as well as the essentiality of the gene in the mammalian stage of the parasite, which is provided by basic research and genetic and proteomic approaches. In this chapter we will discuss how these bioinformatic tools and experimental evaluations can be integrated for the selection of candidate drug targets, and give examples of metabolic and signaling pathways in the parasitic protozoa that can be exploited for rational drug design.

show abstract

LmxMPK4, an essential mitogen-activated protein kinase of Leishmania mexicana is phosphorylated and activated by the STE7-like protein kinase LmxMKK5

Cited by 23 publications

References 50 publications

Trypanosoma brucei: Two mitogen activated protein kinase kinases are dispensable for growth and virulence of the bloodstream form

Trypanosoma brucei: Two mitogen activated protein kinase kinases are dispensable for growth and virulence of the bloodstream form

Enzyme Activity Assays for Protein Kinases: Strategies to Identify Active Substrates

Selection of Molecular Targets for Drug Development Against Trypanosomatids

Contact Info

Product

Resources

About