An aPKC-Exocyst Complex Controls Paxillin Phosphorylation and Migration through Localised JNK1 Activation

The exocyst/aPKC complex controls the spatiotemporal activation of the kinases JNK and ERK at the leading edge of migrating cells and thereby controls the dynamic behaviour of the adhesion protein paxillin during cell migration

Manipulating signal delivery - plasma-membrane ERK activation in aPKC-dependent migration

Members of the PKC superfamily have been implicated in various migratory models and in particular in spatially restricted processes. However, defining the precise local events that underlie the PKC-dependent processes is constrained by the unspecific nature of interventions. Here we address this problem in relation to atypical PKC (aPKC) action, which in conjunction with the exocyst complex controls the polarised delivery of promigratory signals. A drug-dependent recruitment approach was employed to manipulate the local recruitment of signals to the leading edge of migrating cells, under conditions where the aPKC-exocyst control is globally abrogated. We found that activation of ERK but not JNK at focal adhesions recovers the majority of the migratory loss attributed to ERK action, demonstrating a necessary role for active plasma membrane ERK in the downstream signalling of aPKC-dependent migration. The data further show that restored focal adhesion dynamics are a contributing mechanism through which localized ERK activity influences this aPKC-exocyst-dependent migration.</jats:p

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Summary Members of the PKC superfamily have been implicated in various migratory models and in particular in spatially restricted processes. However, defining the precise local events that underlie the PKC-dependent processes is constrained by the unspecific nature of interventions. Here we address this problem in relation to atypical PKC (aPKC) action, which in conjunction with the exocyst complex controls the polarised delivery of promigratory signals. A drug-dependent recruitment approach was employed to manipulate the local recruitment of signals to the leading edge of migrating cells, under conditions where the aPKC-exocyst control is globally abrogated. We found that activation of ERK but not JNK at focal adhesions recovers the majority of the migratory loss attributed to ERK action, demonstrating a necessary role for active plasma membrane ERK in the downstream signalling of aPKC-dependent migration. The data further show that restored focal adhesion dynamics are a contributing mechanism through which localized ERK activity influences this aPKC-exocyst-dependent migration

Molecular pharmacology in a simple model system: Implicating MAP kinase and phosphoinositide signalling in bipolar disorder

Understanding the mechanisms of drug action has been the primary focus for pharmacological researchers, traditionally using rodent models. However, non-sentient model systems are now increasingly being used as an alternative approach to better understand drug action or targets. One of these model systems, the social amoeba Dictyostelium, enables the rapid ablation or over-expression of genes, and the subsequent use of isogenic cell culture for the analysis of cell signalling pathways in pharmacological research. The model also supports an increasingly important ethical view of research, involving the reduction, replacement and refinement of animals in biomedical research. This review outlines the use of Dictyostelium in understanding the pharmacological action of two commonly used bipolar disorder treatments (valproic acid and lithium). Both of these compounds regulate mitogen activated protein (MAP) kinase and inositol phospholipid-based signalling by unknown means. Analysis of the molecular pathways targeted by these drugs in Dictyostelium and translation of discoveries to animal systems has helped to further understand the molecular mechanisms of these bipolar disorder treatments