MINK and TNIK differentially act on Rap2-mediated signal transduction to regulate neuronal structure and AMPA receptor function.
Misshapen/NIKs (Nck-interacting kinases)-related kinase (MINK) and closely related TRAF2/Nck-interacting kinase (TNIK) are proteins that specifically bind to activated Rap2 and are thus hypothesized to relay its downstream signal transduction. Activated Rap2 has been found to stimulate dendritic pruning, reduce synaptic density and cause removal of synaptic AMPA receptors (AMPA-Rs) (Zhu et al., 2005; Fu et al., 2007). Here we report that MINK and TNIK are postsynaptically enriched proteins whose clustering within dendrites is bidirectionally regulated by the activation state of Rap2. Expression of MINK and TNIK in neurons is required for normal dendritic arborization and surface expression of AMPA receptors. Overexpression of a truncated MINK mutant unable to interact with Rap2 leads to reduced dendritic branching and this MINK-mediated effect on neuronal morphology is dependent upon Rap2 activation. While similarly truncated TNIK also reduces neuronal complexity, its effect does not require Rap2 activity. Furthermore, Rap2-mediated removal of surface AMPA-Rs from spines is entirely abrogated by coexpression of MINK, but not TNIK. Thus, although both MINK and TNIK bind GTP-bound Rap2, these kinases employ distinct mechanisms to modulate Rap2-mediated signaling. MINK appears to antagonize Rap2 signal transduction by binding to activated Rap2. We suggest that MINK interaction with Rap2 plays a critical role in maintaining the morphological integrity of dendrites and synaptic transmission.
Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Natasha K
NK
Hussain
Honor
H
Hsin
Richard L
RL
Huganir
Morgan
M
Sheng
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D049229:Dendritic Spines / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*; D009435:Synaptic Transmission / Q000502:physiology; D020668:rap GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
C484268:Kcne1 protein, rat; D024642:Potassium Channels, Voltage-Gated; D018091:Receptors, AMPA; D017346:Protein Serine-Threonine Kinases; C553969:TNIK protein, rat; C116756:RAP2A protein, human; D020668:rap GTP-Binding Proteins