Clutch engagement provides the mechanical resistance that is needed for the actin network to overcome the rearward current of retrograde flow, which in turn allows the plasma membrane to translocate forward. Forces www.selleckchem.com/products/torin-1.html generated by clutch resistance of the F-actin network are transmitted

back to the adhesions, resulting in increased surface traction (Aratyn-Schaus and Gardel, 2010, Brown et al., 2006, Giannone et al., 2009 and Hu et al., 2007). Compelling evidence of the clutch model has been demonstrated in neurons (Bard et al., 2008 and Chan and Odde, 2008). In nascent protrusions that result from clutch engagement, newly polymerized actin primes and positions integrins for activation (Chan and Odde, 2008). Adhesions experiencing increased force undergo higher component turnover (Wolfenson et al., 2011). Together, these create a cycle promoting dynamic fluctuation and positive growth. It is clear that mechanical signaling plays an important role in outgrowth and guidance, but its exact mechanism of controlling overall movement has not yet been determined. Adhesions are dynamic complexes whose turnover is critical for cell movement (Huttenlocher and Horwitz, 2011). Stable adhesions immobilize the cell while lack of adhesion makes it incapable of crawling on a substrate. In a motile growth cone, adhesions assemble and

disassemble to change in number, size, and position Y-27632 supplier (Myers and Gomez, 2011 and Thoumine, 2008). Additionally, the individual adhesion components, including the surface receptors, undergo turnover within the point contacts (Dequidt et al., 2007). Adhesions are protein structures in constant flux, ready

to immediately respond to internal and external signals. Modification of adhesion dynamics can effect overall migration or, if done locally within the growth cone, cause a directional guidance response (Myers and Gomez, 2011, Myers et al., 2011 and Woo and Gomez, 2006). Several traditional signaling pathways that work through focal adhesions have been shown to mediate both attractive and repulsive guidance responses. There are numerous almost reviews that are specifically dedicated to the vast signaling networks that work through adhesions (Kamiguchi, 2007, Kolodkin and Tessier-Lavigne, 2011, Maness and Schachner, 2007 and Myers et al., 2011). In this section, we would like to focus on focal adhesion kinase (FAK), a single, well-studied adhesion protein, to highlight how its complex regulation can induce polar effects in the migrating growth cone. We hope to demonstrate the need to understand the spatiotemporal regulation of adhesive contacts. Focal adhesion kinase (FAK) is a protein-tyrosine kinase that provides a direct link between adhesions and intracellular signaling pathways (Mitra et al., 2005 and Parsons, 2003). FAK is downstream of both extracellular matrix and intracellular signaling components, therefore it is in a position to transduce signals to and from adhesions.