Kinases and regeneration
Kinases regulate most aspects of cell function. As they are very important in cancer, there are many drugs and compounds as well as cDNA and RNAi libraries that can be used to perturb the Kinome. Neuroscientists should exploit these resources.
We have done a large overexpression screen in primary hippocampal neurons (Buchser et al, 2010). Besides identifying interesting individual targets for further study, we did pathway analysis and gene ontology analysis based on the phenotypic data. Guess what? Cancer pathways are very important in regulating neurite growth.
More recently we are using kinase inhibitors (KIs) to identify target (those to inhibit) and liability (those to avoid) kinases to promote regeneration (Al-Ali et al, 2013). This work exploits polypharmacology and KI biochemical profiling data, Maximum Relevance algorithms and Support Vector Machines, followed by RNAi to design a small but informative list of kinases that can be used to predict whether a new compound will enhance neurite growth (watch this space!). Did I mention Hassan's 5 KI, 4 concentration, all combinations experiment? It is sweet*.
*by this, Vance means informative.
Slepak TI, Salay LD, Lemmon VP, Bixby JL. Dyrk kinases regulate phosphorylation of doublecortin, cytoskeletal organization, and neuronal morphology. Cytoskeleton (Hoboken). 2012 69:514-27.
Buchser WJ, Slepak TI, Gutierrez-Arenas O, Bixby JL, Lemmon VP. Kinase/phosphatase overexpression reveals pathways regulating hippocampal neuron morphology. Mol Syst Biol. 2010 Jul 27;6:391.PMID: 20664637
Al-Ali H, Schürer SC, Lemmon VP, Bixby JL. Chemical Interrogation of the Neuronal Kinome Using a Primary Cell-Based Screening Assay. ACS Chem Biol. 2013 8:1027-36
We have done a large overexpression screen in primary hippocampal neurons (Buchser et al, 2010). Besides identifying interesting individual targets for further study, we did pathway analysis and gene ontology analysis based on the phenotypic data. Guess what? Cancer pathways are very important in regulating neurite growth.
More recently we are using kinase inhibitors (KIs) to identify target (those to inhibit) and liability (those to avoid) kinases to promote regeneration (Al-Ali et al, 2013). This work exploits polypharmacology and KI biochemical profiling data, Maximum Relevance algorithms and Support Vector Machines, followed by RNAi to design a small but informative list of kinases that can be used to predict whether a new compound will enhance neurite growth (watch this space!). Did I mention Hassan's 5 KI, 4 concentration, all combinations experiment? It is sweet*.
*by this, Vance means informative.
Slepak TI, Salay LD, Lemmon VP, Bixby JL. Dyrk kinases regulate phosphorylation of doublecortin, cytoskeletal organization, and neuronal morphology. Cytoskeleton (Hoboken). 2012 69:514-27.
Buchser WJ, Slepak TI, Gutierrez-Arenas O, Bixby JL, Lemmon VP. Kinase/phosphatase overexpression reveals pathways regulating hippocampal neuron morphology. Mol Syst Biol. 2010 Jul 27;6:391.PMID: 20664637
Al-Ali H, Schürer SC, Lemmon VP, Bixby JL. Chemical Interrogation of the Neuronal Kinome Using a Primary Cell-Based Screening Assay. ACS Chem Biol. 2013 8:1027-36
| cytoskeleton_2012_slepak.pdf |
| buchser_2010_molecularsystemsbiology.pdf |
| acs_chem._biol._2013_al-ali.pdf |
