TY - JOUR
T1 - Rho-Kinase Phosphorylates PAR-3 and Disrupts PAR Complex Formation
AU - Nakayama, Masanori
AU - Goto, Takaaki M.
AU - Sugimoto, Masayuki
AU - Nishimura, Takashi
AU - Shinagawa, Takafumi
AU - Ohno, Sigeo
AU - Amano, Mutsuki
AU - Kaibuchi, Kozo
N1 - Funding Information:
We thank H. Saya and A. Enomoto for helpful discussion, M. Hoshino for materials, Kaibuchi laboratory members, especially T. Hikita and T. Shinoda, for technical help and preparation of materials, and T. Ishii for secretarial assistance. This research was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), a Grant-in-Aid for Creative Scientific Research from the Japan Society for the Promotion of Science and the MEXT 21st Century Center of Excellence Program, a Research Grant for Nervous and Mental Disorders from the Ministry of Health, Labor and Welfare, and the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO), and CREST Japan Science and Technology Agency.
PY - 2008/2/12
Y1 - 2008/2/12
N2 - A polarity complex of PAR-3, PAR-6, and atypical protein kinase C (aPKC) functions in various cell polarization events. PAR-3 directly interacts with Tiam1/Taim2 (STEF), Rac1-specific guanine nucleotide exchange factors, and forms a complex with aPKC-PAR-6-Cdc42•GTP, leading to Rac1 activation. RhoA antagonizes Rac1 in certain types of cells. However, the relationship between RhoA and the PAR complex remains elusive. We found here that Rho-kinase/ROCK/ROK, the effector of RhoA, phosphorylated PAR-3 at Thr833 and thereby disrupted its interaction with aPKC and PAR-6, but not with Tiam2. Phosphorylated PAR-3 was observed in the leading edge, and in central and rear portions of migrating cells having front-rear polarity. Knockdown of PAR-3 by small interfering RNA (siRNA) impaired cell migration, front-rear polarization, and PAR-3-mediated Rac1 activation, which were recovered with siRNA-resistant PAR-3, but not with the phospho-mimic PAR-3 mutant. We propose that RhoA/Rho-kinase inhibits PAR complex formation through PAR-3 phosphorylation, resulting in Rac1 inactivation.
AB - A polarity complex of PAR-3, PAR-6, and atypical protein kinase C (aPKC) functions in various cell polarization events. PAR-3 directly interacts with Tiam1/Taim2 (STEF), Rac1-specific guanine nucleotide exchange factors, and forms a complex with aPKC-PAR-6-Cdc42•GTP, leading to Rac1 activation. RhoA antagonizes Rac1 in certain types of cells. However, the relationship between RhoA and the PAR complex remains elusive. We found here that Rho-kinase/ROCK/ROK, the effector of RhoA, phosphorylated PAR-3 at Thr833 and thereby disrupted its interaction with aPKC and PAR-6, but not with Tiam2. Phosphorylated PAR-3 was observed in the leading edge, and in central and rear portions of migrating cells having front-rear polarity. Knockdown of PAR-3 by small interfering RNA (siRNA) impaired cell migration, front-rear polarization, and PAR-3-mediated Rac1 activation, which were recovered with siRNA-resistant PAR-3, but not with the phospho-mimic PAR-3 mutant. We propose that RhoA/Rho-kinase inhibits PAR complex formation through PAR-3 phosphorylation, resulting in Rac1 inactivation.
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U2 - 10.1016/j.devcel.2007.11.021
DO - 10.1016/j.devcel.2007.11.021
M3 - Article
C2 - 18267089
AN - SCOPUS:38849122774
SN - 1534-5807
VL - 14
SP - 205
EP - 215
JO - Developmental Cell
JF - Developmental Cell
IS - 2
ER -