Biology Reference
In-Depth Information
So far, durotaxist is an entirely
in vitro
phenomenon with no known example in develop-
ment; it has been mentioned here, briefly, in case it does turn out to be important
in vivo
too.
ATTRACTION BY CONTACT-DRIVEN CELL SIGNAL
TRANSDUCTION
Intergin-containing adhesive complexes contain, in addition to proteins that link them to
the actin cytoskeleton, signalling proteins such as focal adhesion kinase (FAK) that announce
to the rest of the cell the binding of integrins to their external ligands.
16
As well as being acti-
vated by integrin-matrix binding, FAKs are sensitive to mechanical forces at the site of adhe-
sion.
17
Loss of FAK also causes Rho to remain abnormally active when cells are plated on
a substrate to which their integrins bind, and active Rho stabilizes their stress fibres and
adhesive contacts and tends to inhibit turnover of adhesions.
18
There is growing evidence
that FAK signals to Rho by activating the Rho guanidine nucleotide exchange factors,
LARG and PDZ-RhoGEF, which return inactive Rho-GDP to its active Rho-GTP form.
19
Integrin-mediated guidance of cells is therefore likely to be more subtle than simple hapto-
tactic models imply.
Other 'adhesion molecules' are also involved in cell signalling. The molecules NCAM,
N-cadherin and L1 were first identified as homophilic cell adhesion molecules that are
important particularly, but not exclusively, in the nervous system. As well as being adhesive,
each of these molecules can signal its homophilic binding to a similar molecule on another
cell by activating the FGF receptor (FGFR) tyrosine kinase on its own cell.
20
The name of
the receptor notwithstanding, this action is independent of the presence of FGF. If FGFR func-
tion is inhibited, neurons and growing axons lose their ability to respond to NCAM, N-cad-
herin or L1 in culture and
in vivo.
21
At least one pathway linking the FGF receptor to growth
cone morphogenesis has been elucidated. FGFR activation signals via phosphplipase-C-
g
and diacylglycerol lipase to stimulate production of arachidonic acid.
22
In neurites, the pres-
ence of arachidonic acid leads to activation of some isoforms of protein kinase C and conse-
quent phosphorylation of the neural growth-associated protein, GAP43. What is more, this
pathway acts synergistically with free cytoplasmic Ca
2
þ
, so that the phosphorylation of
GAP43 driven by arachidonic acid is much greater in the presence of free Ca
2
þ
.
ref
23
GAP43 is synthesized by neurons as they produce neurites, but not before, and the protein
accumulates in the growth cone. Phosphorylated GAP43 binds to and stabilizes actin poly-
mers, protecting them fromdepolymerization.
24
Local binding of the NCAMon a filopodium,
or on part of a lamellipodium, to NCAM on another cell would therefore cause local phos-
phorylation of GAP43, local stabilization of actin filaments, and an advantage to that filopo-
dium in the competition between filopodia. In support of this idea, antibodies specific for
phosphorylated GAP43 show that phosphorylation correlates with areas of growth cone
advance and unphosphorylated GAP43 correlates with areas of retraction. The adhesion
molecule-FGFR-GAP43 signalling path seems to be separate from that driven by integrins.
Mutation of GAP43 abolishes the ability of NCAM to support elongation of neurites
25
but
they can still elongate normally over laminin,
26
which uses integrin receptors.
The fact that 'cell adhesion molecules' can stimulate neurite outgrowth mainly by signal
transduction, rather than mechanically, is emphasized by the fact that application of soluble
