Slit stimulation recruits Dock and Pak to the roundabout receptor and increases Rac activity to regulate axon repulsion at the CNS midline.
Drosophila Roundabout (Robo) is the founding member of a conserved family of repulsive axon guidance receptors that respond to secreted Slit proteins. Here we present evidence that the SH3-SH2 adaptor protein Dreadlocks (Dock), the p21-activated serine-threonine kinase (Pak), and the Rac1/Rac2/Mtl small GTPases can function during Robo repulsion. Loss-of-function and genetic interaction experiments suggest that limiting the function of Dock, Pak, or Rac partially disrupts Robo repulsion. In addition, Dock can directly bind to Robo's cytoplasmic domain, and the association of Dock and Robo is enhanced by stimulation with Slit. Furthermore, Slit stimulation can recruit a complex of Dock and Pak to the Robo receptor and trigger an increase in Rac1 activity. These results provide a direct physical link between the Robo receptor and an important cytoskeletal regulatory protein complex and suggest that Rac can function in both attractive and repulsive axon guidance.
Fan
Xueping
X
Department of Neuroscience, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
Labrador
Juan Pablo
JP
Hing
Huey
H
Bashaw
Greg J
GJ
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001369:Axons / Q000378:metabolism*; D002490:Central Nervous System / Q000196:embryology / Q000378:metabolism; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006801:Humans; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000235:genetics; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D000097905:Roundabout Proteins
D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D011971:Receptors, Immunologic; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins; D000097905:Roundabout Proteins; C099753:dock protein, Drosophila; C066819:sli protein, Drosophila; C099277:Pak protein, Drosophila