Timing is everything

Cell adhesion to the extracellular matrix elicits a temporal reorganization of the actin cytoskeleton that is regulated first by Rac1 and later by RhoA. The signaling mechanisms controlling late stage RhoA activation are incompletely understood. Net1A is a RhoA/RhoB-specific guanine nucleotide exchange factor that is required for cancer cell motility. The ability of Net1A to stimulate RhoA activation is negatively regulated by nuclear sequestration. However, mechanisms controlling the plasma membrane localization of Net1A had not previously been reported. Recently we have shown that Rac1 activation stimulates plasma membrane relocalization and activation of Net1A. Net1A relocalization is independent of its catalytic activity and does not require its C-terminal pleckstrin homology or PDZ interacting domains. Rac1 activation during cell adhesion stimulates a transient relocalization of Net1A that is terminated by proteasomal degradation of Net1A. Importantly, plasma membrane localization of Net1A is required for efficient myosin light chain phosphorylation, focal adhesion maturation, and cell spreading. These data show for the first time a physiological mechanism controlling Net1A relocalization from the nucleus. They also demonstrate a previously unrecognized role for Net1A in controlling actomyosin contractility and focal adhesion dynamics during cell adhesion.     

Timing is everything in the human embryo

A noninvasive imaging method for predicting how human embryos will develop may improve the success and safety of in vitro fertilization.     

Timing is everything: regulatory overlap in plant cell death

Plant development and defence are intimately connected to programmed cell death (PCD). PCD can occur after environmental cues such as pathogen infection, mechanical damage or abiotic stress. However, PCD also constitutes an essential feature of various aspects of growth and development. Despite the differences in stimuli, the subsequent steps leading to programmed cellular death show considerable commonality, reflecting the essential and overlapping roles of individual regulatory components in these processes. These components can function as positive or negative regulators and can have contrasting functions depending on the form of cell death.     

Timing is everything: regulation of Cdk1 and aneuploidy

The spindle checkpoint ensures the proper partition of the chromosomal content of dividing cells, by controlling the transition from metaphase to anaphase. In a recent issue of Cancer Cell, Vecchione and coworkers report that the protein product of the tumor suppressor gene Lzts1 (Leucine zipper tumor suppressor-1) binds the Cdk1 phosphatase Cdc25C and stabilizes it by protecting it from proteasomal degradation (Vecchione et al., 2007). Partial or complete loss of Lzts1 downregulates Cdc25C and inhibits Cdk1 activity during mitosis, leading to premature transition from metaphase to anaphase.     

Timing is everything the role of kinetics in G protein activation

The binding of a drug to a G-protein coupled receptor initiates a complex series of dynamic events that ultimately leads to a cellular response. In addition to the concentrations of receptor, drug and G-protein, important determinants of the cellular response are the rates at which these species interact. However, most models for G-protein coupled receptor signaling are equilibrium models that neglect the role of reaction kinetics. A kinetic ternary-complex model of signaling through G-protein coupled receptors is presented. We demonstrate that this kinetic model can make significantly different predictions than an equilibrium ternary complex model, which provides a different perspective on multiple aspects of the signal transduction cascade, such as agonist efficacy, the effect of precoupled receptors, and the role of RGS proteins. Incorporation of the reaction kinetics is critical for a complete understanding of signal transduction and will ultimately impact the fields of drug discovery and drug design.     

Timing is everything: international variations in historical sexual partnership concurrency and HIV prevalence

Background

Higher prevalence of concurrent partnerships is one hypothesis for the severity of the HIV epidemic in the countries of Southern Africa. But measures of the prevalence of concurrency alone do not adequately capture the impact concurrency will have on transmission dynamics. The importance of overlap duration and coital exposure are examined here.

Methodology/Principal Findings

We conducted a comparison of data from three studies of sexual behavior carried out in the early 1990s in Uganda, Thailand and the US. Using cumulative concurrency measures, the three countries appeared somewhat similar. Over 50% of both Thai and Ugandan men reported a concurrency within the last three partnerships and over 20% reported a concurrency in the last year, the corresponding rates among US men were nearly 20% for Blacks and Hispanics, and about 10% for other racial/ethnic groups. Concurrency measures that were more sensitive to overlap duration, however, showed large differences. The point prevalence of concurrency on the day of interview was over 10% among Ugandan men compared to 1% for Thai men. Ugandan concurrencies were much longer duration – a median of about two years – than either the Thai (1 day) or US concurrencies (4–9 months across all groups), and involved 5–10 times more coital risk exposure with the less frequent partner. In the US, Blacks and Hispanics reported higher prevalence, longer duration and greater coital exposure than Whites, but were lower than Ugandans on nearly every measure. Together, the differences in the prevalence, duration and coital exposure of concurrent partnerships observed align with the HIV prevalence differentials seen in these populations at the time the data were collected.

Conclusions/Significance

There were substantial variations in the patterns of concurrent partnerships within and between populations. More long-term overlapping partnerships, with regular coital exposure, were found in populations with greater HIV epidemic severity.     

A fibronectin-like molecule is present in the developing cat cerebral cortex and is correlated with subplate neurons

The subplate is a transient zone of the developing cerebral cortex through which postmitotic neurons migrate and growing axons elongate en route to their adult positions within the cortical plate. To learn more about the cellular interactions that occur in this zone, we have examined whether fibronectins (FNs), a family of molecules known to promote migration and elongation in other systems, are present during the fetal and postnatal development of the cat's cerebral cortex. Three different anti-FN antisera recognized a single broad band with an apparent molecular mass of 200-250 kD in antigen-transfer analyses (reducing conditions) of plasma-depleted (perfused) whole fetal brain or synaptosome preparations, indicating that FNs are present at these ages. This band can be detected as early as 1 mo before birth at embryonic day 39. Immunohistochemical examination of the developing cerebral cortex from animals between embryonic day 46 and postnatal day 7 using any of the three antisera revealed that FN-like immunoreactivity is restricted to the subplate and the marginal zones, and is not found in the cortical plate. As these zones mature into their adult counterparts (the white matter and layer 1 of the cerebral cortex), immunostaining gradually disappears and is not detectable by postnatal day 70. Previous studies have shown that the subplate and marginal zones contain a special, transient population of neurons (Chun, J. J. M., M. J. Nakamura, and C. J. Shatz. 1987. Nature (Lond.). 325:617-620). The FN-like immunostaining in the subplate and marginal zone is closely associated with these neurons, and some of the immunostaining delineates them. Moreover, the postnatal disappearance of FN-like immunostaining from the subplate is correlated spatially and temporally with the disappearance of the subplate neurons. When subplate neurons are killed by neurotoxins, FN-like immunostaining is depleted in the lesioned area. These observations show that an FN-like molecule is present transiently in the subplate of the developing cerebral cortex and, further, is spatially and temporally correlated with the transient subplate neurons. The presence of FNs within this zone, but not in the cortical plate, suggests that the extracellular milieu of the subplate mediates a unique set of interactions required for the development of the cerebral cortex.