Open AccessA Rac GTPase-Activating Protein, MgcRacGAP, Is a Nuclear Localizing Signal-Containing Nuclear Chaperone in the Activation of STAT Transcription Factors
Author(s) -
Toshiyuki Kawashima,
Ying Bao,
Yukinori Minoshima,
Yasushi Nomura,
Tomonori Hatori,
Tomohide Hori,
Tatsuo Fukagawa,
Toshiyuki Fukada,
Noriko Takahashi,
Tetsuya Nosaka,
Makoto Inoue,
Tomohiro Sato,
Mutsuko Kukimoto-Niino,
Mikako Shirouzu,
Shigeyuki Yokoyama,
Toshio Kitamura
Publication year - 2009
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.01423-08
Subject(s) - biology , microbiology and biotechnology , nls , nuclear localization sequence , gtpase , phosphorylation , tyrosine phosphorylation , nuclear transport , cell nucleus , cytoplasm
In addition to their pleiotropic functions under physiological conditions, transcription factors STAT3 and STAT5 also have oncogenic activities, but how activated STATs are transported to the nucleus has not been fully understood. Here we show that an MgcRacGAP mutant lacking its nuclear localizing signal (NLS) blocks nuclear translocation of p-STATs both in vitro and in vivo. Unlike wild-type MgcRacGAP, this mutant did not promote complex formation of phosphorylated STATs (p-STATs) with importin α in the presence of GTP-bound Rac1, suggesting that MgcRacGAP functions as an NLS-containing nuclear chaperone. We also demonstrate that mutants of STATs lacking the MgcRacGAP binding site (the strand βb) are hardly tyrosine phosphorylated after cytokine stimulation. Intriguingly, mutants harboring small deletions in the C′-adjacent region (βb-βc loop region) of the strand βb became constitutively active with the enhanced binding to MgcRacGAP. The molecular basis of this phenomenon will be discussed, based on the computer-assisted tertiary structure models of STAT3. Thus, MgcRacGAP functions as both a critical mediator of STAT's tyrosine phosphorylation and an NLS-containing nuclear chaperone of p-STATs.