Mitogen-Activated Protein Kinase Kinase 5 Regulates Proliferation and Biosynthetic Processes in Procyclic Forms of Trypanosoma brucei

Abstract

The pathogenic protozoan T. brucei alternates into distinct developmental stages in the mammalian and insect hosts. The mitogen-activated protein kinase (MAPK) signaling pathways transduce extracellular stimuli into a range of cellular responses, which ultimately lead to the adaptation to the external environment. Here, we combined a loss of function approach with stable isotope labeling with amino acids in cell culture (SILAC)-based mass spectrometry (MS) to investigate the role of the mitogen-activated protein kinase kinase 5 (MKK5) in T. brucei. The silencing of MKK5 significantly decreased the proliferation of procyclic forms of T. brucei. To shed light on the molecular alterations associated with this phenotype, we measured the total proteome and phosphoproteome of cells silenced for MKK5. In the total proteome, we observed a general decrease in proteins related to ribosome and translation as well as down-regulation of several components of the fatty acids biosynthesis pathway. In addition, we observed alterations in the protein levels and phosphorylation of key metabolic enzymes, which point toward a suppression of the oxidative metabolism. Taken together, our findings show that the silencing of MKK5 alters cell growth, energy metabolism, protein and fatty acids biosynthesis in procyclic T. brucei.

Identification of Functional MKK3/6 and MEK1/2 Homologs from Echinococcus granulosus and Investigation of Protoscolecidal Activity of Mitogen-Activated Protein Kinase Signaling Pathway Inhibitors In Vitro and In Vivo

“…The other two inhibitors, PD184352 and U0126, are potent and selective inhibitors with specific activity against MEK1/2-like MAPKKs, and they do not exert effects on related MKK3/6-or MKK4/7-like MAPKKs (38). In parasites such as Plasmodium falciparum, Trypanosoma brucei, and S. mansoni, MAPK pathway members have long been investigated as potential drug targets (30,(39)(40)(41)(42). In addition, the antiparasitic activities of sorafenib, PD184352, and U0126 were assessed previously (43)(44)(45).…”

Molecular mechanism by which Apis cerana cerana MKK6 (AccMKK6)-mediated MAPK cascades regulate the oxidative stress response

“…The MAPK signaling pathway is one of the important signal transduction systems in organisms, and many MKKs have been identified. MKKs are a family of serine/threonine protein kinases that are involved in many cellular responses including cell growth, nervous system development and immunity [17,38]. Previous studies demonstrated that MKKs may play a role in combatting oxidative stress [12].…”