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Sci. STKE, 7 August 2007
Vol. 2007, Issue 398, p. tw282
[DOI: 10.1126/stke.3982007tw282]


Neuronal Development Slit Has Complex Effects

Elizabeth M. Adler

Science's STKE, AAAS, Washington, DC 20005, USA

Developing axons interact with cells and substrate encountered en route to their target through adhesion molecules such as N-cadherin. The repulsive guidance cue Slit acts through the Robo receptor to inhibit N-cadherin-mediated adhesion--and thereby neurite outgrowth--through the phosphorylation-dependent dissociation of beta-catenin from N-cadherin. This occurs in conjunction with the formation of a multimeric complex that includes not only Robo and N-cadherin but also the Abl tyrosine kinase. Rhee et al. found that, after treatment with Slit, Abl and Robo immunoprecipitated from chick neural retina cells together with the adaptor protein Cables (for Cdk5 and Abl enzyme substrate). As the name implies, Cables is also a substrate for Cdk5, and Slit stimulated an increase in the amount of Cdk5 that immunoprecipitated with Abl and with cadherin, whereas it elicited a decrease in cadherin association with the Cdk5 regulatory subunit p35. p35 interacts with beta-catenin, and disruption of the Cdk5-Cables interaction inhibited the Slit-induced loss of beta-catenin and p35 from the N-cadherin complex, as well as inhibiting association of beta-catenin with Cables. In vitro binding assays indicated that Cables bound to beta-catenin and Abl, but not to N-cadherin. Further, Cables and p35 competed with each other for binding to beta-catenin, and Cables knockdown led to an increase in the association of N-cadherin and beta-catenin and a "flattened" phenotype in cells expressing a constitutively active form of Robo. Mutational analysis indicated that Abl phosphorylated beta-catenin on tyrosine 489 (Y489), inhibiting the beta-catenin-N-cadherin interaction. Y489-phosphorylated beta-catenin translocated to the nucleus, where it interacted with the transcription factor Tcf and activated the transcription of a target gene reporter. Thus, Cables appears to play a key role in the formation of the Robo-N-cadherin complex, and release of beta-catenin from N-cadherin allows Slit not only to coordinate axonal guidance and adhesion but also to mediate changes in gene transcription.

J. Rhee, T. Buchan, L. Zukerberg, J. Lilien, J. Balsamo, Cables links Robo-bound Abl kinase to N-cadherin-bound beta-catenin to mediate Slit-induced modulation of adhesion and transcription. Nat. Cell Biol. 9, 883-892 (2007). [PubMed]

Citation: E. M. Adler, Slit Has Complex Effects. Sci. STKE 2007, tw282 (2007).

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