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Mutation of Drosophila focal adhesion kinase induces bang-sensitive behavior and disrupts glial function, axonal conduction and synaptic transmission.

ABSTRACT: The role of the conserved focal adhesion kinase (FAK) family of protein tyrosine kinases in the development and physiological functions of the CNS has long been an area of interest among neuroscientists. In this report, we observe that Drosophila mutants lacking Fak56 exhibit a decreased lifespan, accompanied by a bang-sensitive phenotype, which is characterized by sensitivity to mechanical and high-frequency electrical stimulation. Fak56 mutant animals display lower thresholds and higher rates of seizures in response to electroconvulsive stimuli. Direct measurements of action potential conduction in larval segmental nerves demonstrate a slowed propagation speed and failure during high-frequency nerve stimulation. In addition, neuromuscular junctions in Fak56 mutant animals display transmission blockade during high-frequency activity as a result of action potential failure. Endogenous Fak56 protein is abundant in glial cells ensheathing the axon bundles, and structural alterations of segmental nerve bundles can be observed in mutants. Manipulation of Fak56 function specifically in glial cells also disrupts action potential conduction and neurotransmission, suggesting a glial component in the Fak56 bang-sensitive phenotype. Furthermore, we show that increased intracellular calcium levels result in the dephosphorylation of endogenous Fak56 protein in Drosophila cell lines, in parallel with our observations of highly variable synaptic potentials at a higher Ca2+ level in Fak56 mutant larvae. Together these findings suggest that modulation of Fak56 function is important for action potential propagation and Ca2+-regulated neuromuscular transmission in vivo.

SUBMITTER: Ueda A

PROVIDER: S-EPMC2671471 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Mutation of Drosophila focal adhesion kinase induces bang-sensitive behavior and disrupts glial function, axonal conduction and synaptic transmission.

Ueda Atsushi A Grabbe Caroline C Lee Jihye J Lee Jisue J Palmer Ruth H RH Wu Chun-Fang CF

The European journal of neuroscience 20080606 11

The role of the conserved focal adhesion kinase (FAK) family of protein tyrosine kinases in the development and physiological functions of the CNS has long been an area of interest among neuroscientists. In this report, we observe that Drosophila mutants lacking Fak56 exhibit a decreased lifespan, accompanied by a bang-sensitive phenotype, which is characterized by sensitivity to mechanical and high-frequency electrical stimulation. Fak56 mutant animals display lower thresholds and higher rates ...[more]

PMID: 18540882

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Project description:Cervical carcinomas result from cellular transformation by the human papillomavirus (HPV) E6 and E7 oncogenes which are constitutively expressed in cancer cells. The E6 oncogene degrades p53 thereby modulating a large set of p53 target genes as shown previously in the cervical carcinoma cell line HeLa. Here we show that the TAp63β isoform of the p63 transcription factor is also a target of E6. The p63 gene plays an essential role in skin homeostasis and is expressed as at least six isoforms. One of these isoforms, ΔNp63α, has been found overexpressed in squamous cell carcinomas and is shown here to be constitutively expressed in Caski cells associated with HPV16. We therefore explored the role of p63 in these cells by performing microarray analyses after repression of endogenous E6/E7 expression. Upon repression of the oncogenes, a large set of p53 target genes was found activated together with many p63 target genes related to cell adhesion. However, through siRNA silencing and ectopic expression of various p63 isoforms we demonstrated that TAp63β is involved in activation of this cell adhesion pathway instead of the constitutively expressed ΔNp63α and β. Furthermore, we showed in cotransfection experiments, combined with E6AP siRNA silencing, that E6 induces an accelerated degradation of TAp63β although not through the E6AP ubiquitin ligase used for degradation of p53. Repression of E6 transcription also induces stabilization of endogenous TAp63β in cervical carcinoma cells that lead to an increased concentration of focal adhesions at the cell surface. Consequently, TAp63β is the only p63 isoform suppressed by E6 in cervical carcinoma as demonstrated previously for p53. Down-modulation of focal adhesions through disruption of TAp63β therefore appears as a novel E6-dependent pathway in transformation. These findings identify a major physiological role for TAp63β in anchorage independent growth that might represent a new critical pathway in human carcinogenesis.

Dataset Information

Mutation of Drosophila focal adhesion kinase induces bang-sensitive behavior and disrupts glial function, axonal conduction and synaptic transmission.

Publications

Mutation of Drosophila focal adhesion kinase induces bang-sensitive behavior and disrupts glial function, axonal conduction and synaptic transmission.

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