PX-RICS, a novel splicing variant of RICS, is a main isoform expressed during neural development.
In our previous study, we identified RICS, a novel beta-catenin-interacting protein with the GAP activity toward Cdc42 and Rac1, and found that RICS plays an important role in the regulation of neural functions, including postsynaptic NMDA signaling and neurite outgrowth. Here we report the characterization of an N-terminal splicing variant of RICS, termed PX-RICS, which has additional phox homology (PX) and src homology 3 (SH3) domains in its N-terminal region. The PX domain of PX-RICS interacted specifically with phosphatidylinositol 3-phosphate [PtdIns(3)P], PtdIns(4)P and PtdIns(5)P. Consistent with this binding affinity, PX-RICS was found to be localized at the endoplasmic reticulum (ER), Golgi and endosomes. We also found that wild-type PX-RICS possessed much lower GAP activity than RICS, whereas a mutant form of PX-RICS whose PX domain lacks the binding ability to phosphoinositides (PIs) exhibited the GAP activity comparable to that of RICS. However, PX-RICS and RICS exhibited similar inhibitory effects on neurite elongation of Neuro-2a cells. Furthermore, we demonstrate that PX-RICS is a main isoform expressed during neural development. Our results suggest that PX-RICS is involved in early brain development including extension of axons and dendrites, and postnatal remodeling and fine-tuning of neural circuits.
Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Tomoatsu
T
Hayashi
Toshio
T
Okabe
Yukiko
Y
Nasu-Nishimura
Fumika
F
Sakaue
Susumu
S
Ohwada
Ken
K
Matsuura
Tetsu
T
Akiyama
Tsutomu
T
Nakamura
D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary; D000076122:Disks Large Homolog 4 Protein; D004721:Endoplasmic Reticulum / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009420:Nervous System / Q000196:embryology* / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
C470196:ARHGAP32 protein, human; D015820:Cadherins; C501444:DLG4 protein, human; D018076:DNA, Complementary; D000076122:Disks Large Homolog 4 Protein; C477752:GC-GAP protein, mouse; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C121001:NR2B NMDA receptor; D018129:Phosphatidylinositol Phosphates; D020033:Protein Isoforms; D016194:Receptors, N-Methyl-D-Aspartate; D051176:beta Catenin