Biomedical Engineering Reference
In-Depth Information
depending on the shape of the microfabricated adhesive island and map out ten-
sion field lines within the cell (8,51).
But how does cell mechanics affect cell fate? Cell anchoring to extracellular
matrix substrates, such as these islands, is mediated by cell surface integrin re-
ceptor molecules that cluster within small anchoring sites known as "focal adhe-
sions." Actin filaments insert at these focal sites of attachment between integrins
and the extracellular matrix, and apply traction forces to these adhesions much
like the tension in a tent membrane is transmitted through ropes to the pegs that
anchor it into the ground. These cellular anchoring structures at the cell mem-
brane are also the nucleation sites for the formation of large, multimolecular
complexes of proteins that are involved in signal transduction, and hence medi-
ate cellular information processing (23). Such complexes at adhesion sites facili-
tate the interactions between signaling proteins. For instance, the activation of
many of the signal-transduction molecules, such as the aforementioned ras-raf-
MEK-Erk mitogenic pathway, depends on the configuration of the actin-
cytoskeleton (28), whereas assembly of signaling protein complexes at the focal
site depends on the tension in the actin bundles (11). Thus, focal adhesions also
represent sites of mechanotransduction (24,34): they sense the mechanical ten-
sion of the cell that is modulated in response to the geometry of the environment
(51).
As described above, the 3D shape of molecules dictates their mechanical
and biochemical behavior—another example of emergence from the level of
their component parts (e.g., from amino acids to catalytic enzymes). Impor-
tantly, altering molecular shape through chemical modification or mechanical
distortion alters biochemistry by changing thermodynamic and kinetic parame-
ters (37,40). The biochemical information-processing network of the cell is
therefore governed by physical interactions that depend on the 3D shape and
mechanical properties of the individual molecules and hence on the state of the
cytoskeletal network that they comprise. Thus, structural networks and informa-
tion networks integrate as a result of mechanochemistry. Specifically, mammal-
ian cells contain structures that link cytoskeleton with signaling pathways,
thereby allowing mechanical forces to feed back to regulate cellular information
processing.
The biochemical details as to the precise molecules that transduce the me-
chanical forces into biochemical signaling are still not fully understood, al-
though strong experimental evidence now supports the implication of several
specific signal-transducing proteins (23). However, given the fact that research-
ers commonly strive to uncover all of the "instructive pathways" by which cell
fates are regulated, it appears that, instead of being carried along linear molecu-
lar pathways, information is processed in a distributed manner over the network
of interacting regulatory molecules. Many of these molecules physically associ-
ate with the load-bearing elements of the structural cytoskeletal network that
stabilizes cell shape. If the activities of associated regulatory molecules were to
