PX‐RICS, a novel splicing variant of RICS, is a main isoform expressed during neural development

• Published in: Genes to cells : devoted to molecular & cellular mechanisms 2007-08, Vol.12 (8), p.929-939
• Main Authors: Hayashi, Tomoatsu, Okabe, Toshio, Nasu‐Nishimura, Yukiko, Sakaue, Fumika, Ohwada, Susumu, Matsuura, Ken, Akiyama, Tetsu, Nakamura, Tsutomu
• Format: Article
• Language: English
• Subjects: Alternative Splicing - genetics; Amino Acid Sequence; Animals; beta Catenin - metabolism; Cadherins - metabolism; Cell Line; Cloning, Molecular; Disks Large Homolog 4 Protein; DNA, Complementary; Endoplasmic Reticulum - metabolism; Endosomes - metabolism; Golgi Apparatus - metabolism; GTPase-Activating Proteins - chemistry; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Membrane Proteins - metabolism; Mice; Molecular Sequence Data; Nervous System - embryology; Nervous System - metabolism; Neurites - metabolism; Phosphatidylinositol Phosphates - metabolism; Protein Isoforms - chemistry; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Structure, Tertiary; Protein Transport; Receptors, N-Methyl-D-Aspartate - metabolism
• ISSN: 1356-9597; 1365-2443
• DOI: 10.1111/j.1365-2443.2007.01101.x

In our previous study, we identified RICS, a novel β‐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.