RAS signalling through PI3-Kinase controls cell migration via modulation of Reelin expression.

RAS signalling through phosphoinositide 3-kinase (PI3-Kinase) has been shown to have an essential role in tumour initiation and maintenance. RAS also regulates cell motility and tumour invasiveness, but the role of direct RAS binding to PI3-Kinase in this remains uncertain. Here, we provide evidence that disruption of RAS interaction with PI3-Kinase p110α decreases cell motility and prevents activation of Rac GTPase. Analysis of gene expression in cells lacking RAS interaction with p110α reveals increased levels of the extracellular matrix glycoprotein Reelin and activation of its downstream pathway resulting in upregulation of E-cadherin expression. Induction of the Reelin/E-cadherin axis is also observed in Kras mutant lung tumours that are regressing due to blockade of RAS interaction with PI3-Kinase. Furthermore, loss of Reelin correlates with decreased survival of lung and breast cancer patients. Reelin thus plays a role in restraining RAS and PI3-kinase promotion of cell motility and potentially tumour metastasis

Parkinson disease loci in the mid-western Amish

Previous evidence has shown that Parkinson disease (PD) has a heritable component, but only a small proportion of the total genetic contribution to PD has been identified. Genetic heterogeneity complicates the verification of proposed PD genes and the identification of new PD susceptibility genes. Our approach to overcome the problem of heterogeneity is to study a population isolate, the mid-western Amish communities of Indiana and Ohio. We performed genome-wide association and linkage analyses on 798 individuals (31 with PD), who are part of a 4,998 member pedigree. Through these analyses, we identified a region on chromosome 5q31.3 that shows evidence of association (p-value < 1 × 10(−4)) and linkage (multipoint HLOD = 3.77). We also found further evidence of linkage on chromosomes 6 and 10 (multipoint HLOD 4.02 and 4.35 respectively). These data suggest that locus heterogeneity, even within the Amish, may be more extensive than previously appreciated