Neuronal Development

Slit Has Complex Effects

Science's STKE  07 Aug 2007:
Vol. 2007, Issue 398, pp. tw282
DOI: 10.1126/stke.3982007tw282

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 β-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 β-catenin, and disruption of the Cdk5-Cables interaction inhibited the Slit-induced loss of β-catenin and p35 from the N-cadherin complex, as well as inhibiting association of β-catenin with Cables. In vitro binding assays indicated that Cables bound to β-catenin and Abl, but not to N-cadherin. Further, Cables and p35 competed with each other for binding to β-catenin, and Cables knockdown led to an increase in the association of N-cadherin and β-catenin and a "flattened" phenotype in cells expressing a constitutively active form of Robo. Mutational analysis indicated that Abl phosphorylated β-catenin on tyrosine 489 (Y489), inhibiting the β-catenin-N-cadherin interaction. Y489-phosphorylated β-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 β-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 β-catenin to mediate Slit-induced modulation of adhesion and transcription. Nat. Cell Biol. 9, 883-892 (2007). [PubMed]