A Src-astic response to mounting tension

Abstract

The nerve growth cone binds to a complex array of guidance cues in its local environment that influence cytoskeletal interactions to control the direction of subsequent axon outgrowth. How this occurs is a critical question and must certainly involve signal transduction pathways. The paper by Suter and Forscher (2001)(this issue) begins to address how one such pathway, an Src family tyrosine kinase, enhances cytoskeletal linkage to apCAM, a permissive extracellular cue for Aplysia growth cones. Interestingly, they show that applied tension increases this kinase's localized phosphorylation that in turn further strengthens linkage. This suggests a potential positive feedback mechanism for amplifying and discriminating guidance information to guide growth cone motility.

Figure 1.

Tension strengthens cytoskeletal linkage to apCAM via an Src family kinase, a positive feedback mechanotransduction. (a) In response to tension applied to a restrained AntiapCAM-coated bead (large green circle) attached to apCAM (red cylinders), an Src family kinase (yellow hexagon) is recruited and activated to further increase linkage between apCAM and actin filaments (checked rectangle) via a molecular clutch (blue square). Actin filaments are in turn connected to microtubules (cobbled rectangle). This mechanotransduction establishes a positive feedback that increases cytoskeletal coupling in response to applied tension (gray curved arrows) and may guide subsequent axon outgrowth. (b) The positive feedback observed in Fig. 1 a may have a role in amplifying differential responses to concentration or interconnectivity of guidance cues. Such mechanisms may allow integration of different cues such as CAMs (red cylinders) and extracellular matrix (orange crosses). Differences in tension could locally enhance the clutch at either CAMs or integrins (light blue rectangles) via an Src family kinase (yellow hexagons). The strength of binding of cues or the compliance of their underlying substrate could increase tension to further enhance coupling at that site. This positive feedback mechanotransduction (gray curved arrows) would act both as a signal amplifier and more importantly a discriminator. This would enhance cytoskeletal movement toward regions of higher effective binding or compliance resulting in a net guidance decision.

Figure 1.

Tension strengthens cytoskeletal linkage to apCAM via an Src family kinase, a positive feedback mechanotransduction. (a) In response to tension applied to a restrained AntiapCAM-coated bead (large green circle) attached to apCAM (red cylinders), an Src family kinase (yellow hexagon) is recruited and activated to further increase linkage between apCAM and actin filaments (checked rectangle) via a molecular clutch (blue square). Actin filaments are in turn connected to microtubules (cobbled rectangle). This mechanotransduction establishes a positive feedback that increases cytoskeletal coupling in response to applied tension (gray curved arrows) and may guide subsequent axon outgrowth. (b) The positive feedback observed in Fig. 1 a may have a role in amplifying differential responses to concentration or interconnectivity of guidance cues. Such mechanisms may allow integration of different cues such as CAMs (red cylinders) and extracellular matrix (orange crosses). Differences in tension could locally enhance the clutch at either CAMs or integrins (light blue rectangles) via an Src family kinase (yellow hexagons). The strength of binding of cues or the compliance of their underlying substrate could increase tension to further enhance coupling at that site. This positive feedback mechanotransduction (gray curved arrows) would act both as a signal amplifier and more importantly a discriminator. This would enhance cytoskeletal movement toward regions of higher effective binding or compliance resulting in a net guidance decision.