Guidance by Chemotaxis - Mechanisms of Morphogenesis - page 95

To sum up, slow diffusion and fast destruction create steep gradients while fast diffusion
and slow destruction create shallow ones.
The diffusion constants of some real signalling molecules have been determined experi-
mentally and they differ by orders of magnitude. Large proteins that associate with extracel-
lular matrices have D values of less than 1 m m 2 /s, soluble proteins have D values around
10 m m 2 /s ref2 while small molecules such as cAMP have D values 100 m m 2 /s. refs3,4 For a given

rate of destruction, larger molecules produce steeper gradients. Rates of destruction can alter
according to context, however, so that a small molecule such as cAMP may act as a shallow-
gradient, long-range signalling molecule extracellularly where it is relatively long-lived, or as
a steep-gradient signalling molecule in the cytoplasm where it is quickly destroyed.
These are general principles of chemotactic gradients, but the ultra-simple model system
used to demonstrate them mathematically is not typical of real biological fields. In life, the
arrangement of the source cells can be complicated, the diffusion 'constant' may in fact
vary with direction (as when tissues provide channels to facilitate diffusion in one direction
and barriers to impede it in another), and the gradient may be altered by the very cells that
are migrating along it; an example of this will be discussed below.

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READING THE CHEMOTACTIC GRADIENT

Chemotactic signals normally act over a range that is large compared with the size of an
individual cell. That means that their space constant, l , is large and the gradient correspond-
ingly shallow. For typical chemotactic gradients, the difference between concentrations at the
front and at the back of a cell is less than 2 percent. 5 Such subtlety presents the cell with
a formidable problem in navigation. In the systems that have been studied in detail d mainly
the aggregating myxamoebae of Dictyostelium discoideum but also a few vertebrate cell types
such as neutrophils d the problem seems to be solved by re-encoding the shallow external
gradient as a steep internal one, and using feedback to accurately control the direction of
that internal gradient.
Aggregating myxamoebae of D. discoideum migrate chemotactically towards a source of
cyclic adenosine monophosphate (cAMP), which they detect by means of a serpentine trans-
membrane receptor, cAR1. cAR1 functions as a conventional G-protein-coupled receptor; its
binding by extracellular cAMP causes it to activate and release its bound heterotrimeric G
protein G a 2 bg complex initiates several signal transduction

cascades, one of the most significant of which (from the point of view of chemotaxis) results
in the activation of PI-3-kinase. PI-3-kinase phosphorylates the phospholipid PI(4,5)P 2 ,
a minor component of the inner face of the plasma membrane, to produce PI(3,4,5)P 3 .
PI(3,4,5)P 3 is a ligand for the plekstrin homology (PH) domains that are a feature of many
signal transduction proteins, and these PH domain-containing proteins therefore become
located and activated at regions of membrane where PI(3,4,5)P 3 is present. The parts of the
cell that are high in PI(3,4,5)P 3 produce lamellipodia, by a mechanism that will be discussed
later. This regulatory effect of PI(3,4,5)P 3 has been demonstrated dramatically in other cell
types such as vertebrate fibroblasts and neutrophils, which can be induced to activate lamel-
lipodia and move in response to a membrane-permeable analogue of PI(3,4,5)P 3 in the
absence of any other directional cues. 6,7

(see Figure 9.3 ). The G a 2 bg