Reduction of microtubule catastrophe events by LIS1, platelet-activating factor acetylhydrolase subunit.
Forming the structure of the human brain involves extensive neuronal migration, a process dependent on cytoskeletal rearrangement. Neuronal migration is believed to be disrupted in patients exhibiting the developmental brain malformation lissencephaly. Previous studies have shown that LIS1, the defective gene found in patients with lissencephaly, is a subunit of the platelet-activating factor acetylhydrolase. Our results indicated that LIS1 has an additional function. By interacting with tubulin it suppresses microtubule dynamics. We detected LIS1 interaction with microtubules by immunostaining and co-assembly. LIS1-tubulin interactions were assayed by co-immunoprecipitation and by surface plasmon resonance changes. Microtubule dynamic measurements in vitro indicated that physiological concentrations of LIS1 indeed reduced microtubule catastrophe events, thereby resulting in a net increase in the maximum length of the microtubules. Furthermore, the LIS1 protein concentration in the brain, measured by quantitative Western blots, is high and is approximately one-fifth of the concentration of brain tubulin. Our new findings show that LIS1 is a protein exhibiting several cellular interactions, and the interaction with the cytoskeleton may prove to be the mode of transducing a signal generated by platelet-activating factor. We postulate that the LIS1-cytoskeletal interaction is important for neuronal migration, a process that is defective in lissencephaly patients.
Sapir
T
T
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Elbaum
M
M
Reiner
O
O
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001921:Brain / Q000002:abnormalities; D001923:Brain Chemistry; D006801:Humans; D008869:Microtubule-Associated Proteins; D008870:Microtubules / Q000473:pathology*; D008954:Models, Biological; D009474:Neurons / Q000473:pathology; D010741:Phospholipases A / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000494:pharmacology; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014404:Tubulin / Q000378:metabolism*
D008869:Microtubule-Associated Proteins; D010972:Platelet Activating Factor; D011506:Proteins; D014404:Tubulin; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human