Cables links Robo-bound Abl kinase to N-cadherin-bound beta-catenin to mediate Slit-induced modulation of adhesion and transcription.
Binding of the secreted axon guidance cue Slit to its Robo receptor results in inactivation of the neural, calcium-dependent cell-cell adhesion molecule N-cadherin, providing a rapid epigenetic mechanism for integrating guidance and adhesion information. This requires the formation of a multimolecular complex containing Robo, Abl tyrosine kinase and N-cadherin. Here we show that on binding of Slit to Robo, the adaptor protein Cables is recruited to Robo-associated Abl and forms a multimeric complex by binding directly to N-cadherin-associated beta-catenin. Complex formation results in Abl-mediated phosphorylation of beta-catenin on tyrosine 489, leading to a decrease in its affinity for N-cadherin, loss of N-cadherin function, and targeting of phospho-Y489-beta-catenin to the nucleus. Nuclear beta-catenin combines with the transcription factor Tcf/Lef and activates transcription. Thus, Slit-induced formation of the Robo-N-cadherin complex results in a rapid loss of cadherin-mediated adhesion and has more lasting effects on gene transcription.
Rhee
Jinseol
J
Department of Biological Sciences, The University of Iowa, Iowa City, Iowa 52242-1324, USA.
Buchan
Tim
T
Zukerberg
Lawrence
L
Lilien
Jack
J
Balsamo
Janne
J
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002642:Chick Embryo; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D006801:Humans; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000166:cytology; D014158:Transcription, Genetic; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000097905:Roundabout Proteins
D015820:Cadherins; D002352:Carrier Proteins; D051360:Cyclin-Dependent Kinase 5; D016213:Cyclins; D029721:Drosophila Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D021122:Protein Subunits; D016315:Proto-Oncogene Proteins c-abl; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D051176:beta Catenin; D000097905:Roundabout Proteins; C066819:sli protein, Drosophila