Lysophosphatidic acid induces cell migration through the selective activation of Akt1

Akt plays pivotal roles in many physiological responses including growth, proliferation, survival, metabolism, and migration. In the current studies, we have evaluated the isoform-specific role of akt in lysophosphatidic acid (LPA)-induced cell migration. Ascites from ovarian cancer patients (AOCP) induced mouse embryo fibroblast (MEF) cell migration in a dose-dependent manner. On the other hand, ascites from liver cirrhosis patients (ALCP) did not induce MEF cell migration. AOCP-induced MEF cell migration was completely blocked by pre-treatment of cells with LPA receptor antagonist, Ki16425. Both LPA- and AOCP-induced MEF cell migration was completely attenuated by PI3K inhibitor, LY294002. Furthermore, cells lacking Akt1 displayed defect in LPA-induced cell migration. Re-expression of Akt1 in DKO (Akt1(-/-)Akt2(-/-)) cells restored LPA-induced cell migration, whereas re-expression of Akt2 in DKO cells could not restore the LPA-induced cell migration. Finally, Akt1 was selectively phosphorylated by LPA and AOCP stimulation. These results suggest that LPA is a major factor responsible for AOCP-induced cell migration and signaling specificity of Akt1 may dictate LPA-induced cell migration.

Sexual selection, redundancy and survival of the most beautiful.

A model is described of a highly redundant complex organism that has overlapping banks of genes such that each vital function is specified by several different genetic systems. This generates a synergistic profile linking probability of survival to the number of deleterious mutations in the genome. Computer models show that there is a dynamic interaction between the mean number of new deleterious mutations per generation (X), the mean number of deleterious mutations in the genome of the population (Y) and percentage zygote survival (Zs). Increased X leads to increased Y and a fall in Zs but it takes several generations before a new equilibrium is reached. If sexual attraction is influenced by the number of deleterious mutations in the genome of individuals then Y is reduced and Zs increased for any given value of X. This fall in Y and rise in Zs is more marked in polygamous than monogamous mating systems. The model is specified such that deleterious mutations can occur without any observable or measurable effect on function. Thus sexual selection, in this organism, for low levels of deleterious mutations cannot be based on assessment of performance. Instead it is based on a simple symmetrical surface pattern that is flawlessly reproduced by organisms with no deleterious mutations, but is less than perfect, and therefore less attractive, if genetic systems have been deleted. A complex vital task requires a system with a high level of redundancy that acts so that the loss of one component has no observable effect and therefore cannot be used for sexual selection. The reproduction of a beautiful surface pattern also requires a low error, high redundancy genetic system; however, in this case there is advantage if a single deleterious mutation produces a recognisable change. This leads to the conclusion that sexual selection and sexual attraction should be based on beauty rather than utility, and explains the common observation in nature that it is the most beautiful that survive.

The conservation of redundancy in genetic systems: effects of sexual and asexual reproduction.

The relationship between probability of survival and the number of deleterious mutations in the genome is investigated using three different models of highly redundant systems that interact with a threatening environment. Model one is a system that counters a potentially lethal infection; it has multiple identical components that act in sequence and in parallel. Model two has many different overlapping components that provide threefold coverage of a large number of vital functions. The third model is based on statistical decision theory: an ideal detector, following an optimum decision strategy, makes crucial decisions in an uncertain world. The probability of a fatal error is reduced by a redundant sampling system, but the chance of error rises as the system is impaired by deleterious mutations. In all three cases the survival profile shows a synergistic pattern in that the probability of survival falls slowly and then more rapidly. This is different than the multiplicative or independent survival profile that is often used in mathematical models. It is suggested that a synergistic profile is a property of redundant systems. Model one is then used to study the conservation of redundancy during sexual and asexual reproduction. A unicellular haploid organism reproducing asexually retains redundancy when the mutation rate is very low (0.001 per cell division), but tends to lose high levels of redundancy if the mutation rate is increased (0.01 to 0.1 per cell division). If a similar unicellular haploid organism has a sexual phase then redundancy is retained for mutation rates between 0.001 and 0.1 per cell division. The sexual organism outgrows the asexual organism when the above mutation rates apply. If they compete for finite resources the asexual organism will be extinguished. Variants of the sexual organism with increased redundancy will outgrow those with lower levels of redundancy and the sexual process facilitates the evolution of more complex forms. There is a limit to the extent that complexity can be increased by increasing the size of the genome and in asexual organisms this leads to progressive accumulation of mutations with loss of redundancy and eventual extinction. If complexity is increased by using genes in new combinations, the asexual form can reach a stable equilibrium, although it is associated with some loss of redundancy. The sexual form, by comparison, can survive, with retention of redundancy, even if the mutation rate is above one per generation. The conservation and evolution of redundancy, which is essential for complexity, depends on the sexual process of reproduction.

GPI phospholipase C from Trypanosoma brucei causes a GPI-negative phenotype in Leishmania major: I. Implications for GPI-negative mammalian cells; II. Compartmentalization of two GPI biosynthetic pathways

The major surface macromolecules of the protozoan parasite Leishmania major, gp63 (a metalloprotease), and lipophosphoglycan (a polysaccharide) are glycosylphosphatidylinositol (GPI)-anchored. We expressed a cytoplasmic glycosylphosphatidylinositol phospholipase C (GPIPLC) in L. major in order to examine the topography of the protein-GPI and polysaccharide-GPI pathways. In L. major cells expressing GPIPLC cell-associated gp63 could not be detected in immunoblots, gp63 was secreted into the culture medium without ever receiving a GPI anchor. Putative protein-GPI intermediates LP-1 and LP-2 decreased about 10-fold. In striking contrast, lipophosphoglycan levels were unaltered. We conclude that reactions specific to the polysaccharide-GPI pathway are compartmentalalized within the endoplasmic reticulum, thereby sequestering those intermediates from GPIPLC cleavage. Protein-GPI synthesis, at least up to production of Man (1Ó6)Man(1Ó4)GlcN(1Ó6)-myo-inositol-1-phospholipid, is cystolic. To our knowledge, this represents the first use of a catabolic enzyme, in vivo, to elucidate the topography of biosynthetic pathways. Intriguingly, the phenotype of GPIPLC-expressing L. major, secretion of proteins with GPI addition signals, and depletion of protein-GPI anchor precursors, is similar to that of some protein-GPI mutants in higher eukaryotes. These findings have implications for paroxysmal nocturnal hemoglobinuria and Thy-1-negative T-lymphoma