Grit, a GTPase-activating protein for the Rho family, regulates neurite extension through association with the TrkA receptor and N-Shc and CrkL/Crk adapter molecules.
Neurotrophins are key regulators of the fate and shape of neuronal cells and act as guidance cues for growth cones by remodeling the actin cytoskeleton. Actin dynamics is controlled by Rho GTPases. We identified a novel Rho GTPase-activating protein (Grit) for Rho/Rac/Cdc42 small GTPases. Grit was abundant in neuronal cells and directly interacted with TrkA, a high-affinity receptor for nerve growth factor (NGF). Another pool of Grit was recruited to the activated receptor tyrosine kinase through its binding to N-Shc and CrkL/Crk, adapter molecules downstream of activated receptor tyrosine kinases. Overexpression of the TrkA-binding region of Grit inhibited NGF-induced neurite elongation. Further, we found some tendency for neurite promotion in full-length Grit-overexpressing PC12 cells upon NGF stimulation. These results suggest that Grit, a novel TrkA-interacting protein, regulates neurite outgrowth by modulating the Rho family of small GTPases.
Nakamura
Takeshi
T
Department of Molecular Genetics, National Institute for Longevity Sciences, Program of Protecting the Brain, CREST, JST, Oobu, Aichi 474-8522, Japan.
Komiya
Misako
M
Sone
Kiyoaki
K
Hirose
Eiji
E
Gotoh
Noriko
N
Morii
Hiroshi
H
Ohta
Yasutaka
Y
Mori
Nozomu
N
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D020690:GTPase-Activating Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D008969:Molecular Sequence Data; D020932:Nerve Growth Factor / Q000378:metabolism; D016501:Neurites / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010802:Phylogeny; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050737:Proto-Oncogene Proteins c-crk; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000502:physiology; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3; D020798:Two-Hybrid System Techniques; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D018909:src Homology Domains
C470196:ARHGAP32 protein, human; D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; C493872:Crk protein, rat; D020690:GTPase-Activating Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D011993:Recombinant Fusion Proteins; C122029:SHC3 protein, human; D055765:Shc Signaling Adaptor Proteins; C485683:Shc3 protein, rat; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3; C085379:rho GTPase-activating protein; D020932:Nerve Growth Factor; D011505:Protein-Tyrosine Kinases; D020917:Receptor, trkA; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein