The Rac1 guanine nucleotide exchange factor Tiam1 mediates EphB receptor-dependent dendritic spine development.
Dendritic spines are small, actin-rich protrusions on the surface of dendrites that receive the majority of excitatory synaptic inputs in the brain. The formation and remodeling of spines, processes that underlie synaptic development and plasticity, are regulated in part by Eph receptor tyrosine kinases. However, the mechanism by which Ephs regulate actin cytoskeletal remodeling necessary for spine development is not fully understood. Here, we report that the Rac1 guanine nucleotide exchange factor Tiam1 interacts with the EphB2 receptor in a kinase-dependent manner. Activation of EphBs by their ephrinB ligands induces the tyrosine phosphorylation and recruitment of Tiam1 to EphB complexes containing NMDA-type glutamate receptors. Either knockdown of Tiam1 protein by RNAi or inhibition of Tiam1 function with a dominant-negative Tiam1 mutant blocks dendritic spine formation induced by ephrinB1 stimulation. Taken together, these findings suggest that EphBs regulate spine development in part by recruiting, phosphorylating, and activating Tiam1. Tiam1 can then promote Rac1-dependent actin cytoskeletal remodeling required for dendritic spine morphogenesis.
Tolias
Kimberley F
KF
Neurobiology Program, Children's Hospital, and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Bikoff
Jay B
JB
Kane
Christina G
CG
Tolias
Christos S
CS
Hu
Linda
L
Greenberg
Michael E
ME
D000818:Animals; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism*; D036387:Ephrin-B1 / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000187:drug effects; D034622:RNA Interference; D051381:Rats; D020318:Rats, Long-Evans; D036081:Receptors, Eph Family / Q000737:chemistry / Q000378:metabolism*; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D036387:Ephrin-B1; D020662:Guanine Nucleotide Exchange Factors; D009363:Neoplasm Proteins; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513259:Tiam1 protein, rat; D019000:Phosphotyrosine; D036081:Receptors, Eph Family; D020830:rac1 GTP-Binding Protein