Receptor-ligand interactions

Turing models have been proposed to explain the emergence of digits during limb development. However,
so far the molecular components that would give rise to Turing patterns are elusive. We have recently shown
that a particular type of receptor-ligand interaction can give rise to Schnakenberg-type Turing patterns,
which reproduce patterning during lung and kidney branching morphogenesis. Recent knockout
experiments have identified Smad4 as a key protein in digit patterning.Weshow here that the BMP-receptor
interaction meets the conditions for a Schnakenberg-type Turing pattern, and that the resulting model
reproduces available wildtype and mutant data on the expression patterns of BMP, its receptor, and Fgfs in
the apical ectodermal ridge (AER) when solved on a realistic 2D domain that we extracted from limb bud
images of E11.5 mouse embryos. We propose that receptor-ligand-based mechanisms serve as a molecular
basis for the emergence of Turing patterns in many developing tissues.

Cell signaling systems sense and respond to ligands that bind cell surface receptors. These systems often respond to changes in the concentration of extracellular ligand more rapidly than the ligand equilibrates with its receptor. We demonstrate, by modeling and experiment, a general “systems level” mechanism cells use to take advantage of the information present in the early signal, before receptor binding reaches a new steady state. This mechanism, pre- equilibrium sensing and signaling (PRESS), operates in signaling sys- tems in which the kinetics of ligand-receptor binding are slower than the downstream signaling steps, and it typically involves transient activation of a downstream step. In the systems where it operates, PRESS expands and shifts the input dynamic range, allowing cells to make different responses to ligand concentrations so high as to be otherwise indistinguishable. Specifically, we show that PRESS applies to the yeast directional polarization in response to pheromone gra- dients. Consideration of preexisting kinetic data for ligand-receptor interactions suggests that PRESS operates in many cell signaling sys- tems throughout biology. The same mechanism may also operate at other levels in signaling systems in which a slow activation step cou- ples to a faster downstream step.

Cells are known to respond to physical cues from their microenvironment such as matrix rigidity. Discrete adhesive ligands within flexible strands of fibronectin connect cell surface integrins to the broader extracellular matrix and are thought to mediate mechanosensing through the cytoskeleton-integrin-ECM linkage. We set out to determine if adhesive ligand tether length is another physical cue that cells can sense. Substrates were covalently modified with adhesive arginylglycylaspartic acid (RGD) ligands coupled with short (9.5 nm), medium (38.2 nm) and long (318 nm) length inert polyethylene glycol tethers. The size and length of focal adhesions of human foreskin fibroblasts gradually decreased from short to long tethers. Furthermore, we found cell adhesion varies in a linker length dependent manner with a remarkable 75% reduction in the density of cells on the surface and a 50% reduction in cell area between the shortest and longest linkers. We also report the interplay between RGD ligand concentration and tether length in determining cellular spread area. Our findings show that without varying substrate rigidity or ligand density, tether length alone can modulate cellular behaviour. It is known that cells are able to sense the rigidity of their microenvironment as illustrated by their differential behaviour when cultured on soft versus stiff substrates. Cell differentiation 1–3 , rate of DNA synthesis 4 , apoptosis 4 , traction forces 4 , motility 5–8 and spread area 2,4,5,7–11 have all been shown to be modulated by changes in substrate rigidity. It has also been demonstrated that transformed cancer cells respond differently to substrate stiffness compared to normal cells 4,12–14. Furthermore, the density of extracellular matrix (ECM) proteins such as collagen and fibronectin play a major role in determining cell behaviour 9,15–17. In order for cells to sense the rigidity of the ECM, they must first form linkages with ECM proteins via trans-membrane integrin receptors 18. Fibronectin is an ECM protein that connects to cell surface integrins via a discrete section along its length containing the adhesive RGD ligand 19,20. With the rest of the fibronectin protein playing a passive role in adhesion, a picture emerges of cells tethered to the matrix via thin and flexible strands of varying length. Within this scenario, we considered the possibility that cells are receptive not only to ECM rigidity and adhesive ligand density but also to the length of the local tether to which the ligand attaches to the broader ECM microenvironment. It was previously argued that, on poly(acrylamide) and poly(dimethylsiloxane) substrates functionalized with ECM proteins, cellular responses due to modulation of substrate stiffness were due to concomitantly modifying the fibronectin or collagen tether density, which resulted in substantial changes in nanoscale mechanical properties 11. Subsequently, it was found that varying the apparent porosity of poly(acrylamide) gels in order to control such tethering density did not result in changes in cell behaviour 17. This indicates that apparent porosity alone is not sufficient to account for the observations made; however, the approach developed did not permit the direct measurement of the density of tethers between the matrix and deposited ECM proteins. Notably, it was not possible to vary the apparent porosity without altering the density of polymer chains in the sample, which is expected

The tripeptide glycine-proline-glutamate (GPE) is the naturally cleaved N-terminal tripeptide of insulin-like growth factor-1 (IGF-1) in brain tissues by an acid protease. Although GPE does not bind to IGF-1 receptors and its mode of action is not clear, in vitro studies have demonstrated its ability to stimulate acetylcholine and dopamine release, as well as to protect neurones from diverse induced brain injures. More importantly, GPE has been shown to have potent neuroprotective effects in numerous animal models of hypoxic-ischemic brain injury and neurodegenerative diseases such as Parkinsons, Alzheimers and Huntingtons diseases. As a consequence, GPE was suggested to be a potential target for the rational design of neuroprotective agents. Unfortunately, the use of GPE as a therapeutic agent is limited because of its unfavorable biochemical and pharmacokinetic properties. This review will focus on structural modifications performed on the GPE molecule in order to obtain bioactive analogues with increased pharmacokinetic profile useful for the treatment of central nervous system (CNS) injures and neurodegenerative disorders.