A lysophosphatidic acid receptor lacking the PDZ-binding domain is constitutively active and stimulates cell proliferation

作者：Shano Shinya; Hatanaka Kazuki; Ninose Shinsuke; Moriyama Ryutaro; Tsujiuchi Toshifumi; Fukushima Nobuyuki^*

来源：Biochimica et Biophysica Acta-Molecular Cell Research, 2008, 1783(5): 748-759.

DOI：10.1016/j.bbamcr.2007.11.013

• lysophosphatidic acid receptor
• PDZ-binding domain
• phosphoinositide 3-kinase
• Akt
• Rho
• oncogenic signal

Lysophosphatidic acid (LPA) is an extracellular signaling lipid that regulates cell proliferation, survival, and motility of normal and cancer cells. These effects are produced through G protein-coupled LPA receptors, LPA(1) to LPA(5). We generated an LPA(1) mutant lacking the SerValVal sequence of the C-terminal PDZ-binding domain to examine the role of this domain in intracellular signaling and other cellular functions. B103 neuroblastoma cells expressing the mutant LPA(1) showed rapid cell proliferation and tended to form colonies under serum-free conditions. The enhanced cell proliferation of the mutant cells was inhibited by exogenous expression of the plasmids inhibiting G proteins including G(beta gamma), G(alpha i) and G(alpha q) or G(alpha 12/13), or treatment with pertussis toxin, phosphoinositide 3-kinase (PI3K) inhibitors or a Rho inhibitor. We confirmed that the PI3K-Akt and Rho pathways were intrinsically activated in mutant cells by detecting increases in phosphorylated Akt in western blot analyses or by directly measuring Rho activity. Interestingly, expression of the mutant LPA(1) in non-tumor mouse fibroblasts induced colony formation in a clonogenic soft agar assay, indicating that oncogenic pathways were activated. Taken together, these observations suggest that the mutant LPA(1) constitutively activates the G protein signaling leading to PI3K-Akt and Rho pathways, resulting in enhanced cell proliferation.

• 出版日期2008-5