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TRANSLATIONAL PHYSIOLOGY

LPA₂ receptor mediates mitogenic signals in human colon cancer cells

¹Departments of Medicine and Physiology, ²Department of Pharmacology, and ³Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia

Submitted 14 December 2004 ; accepted in final form 15 February 2005

ABSTRACT

Lysophosphatidic acid (LPA) is a mediator of multiple cellular responses. LPA mediates its effects predominantly through the G protein-coupled receptors LPA₁, LPA₂, and LPA₃. In the present work, we studied LPA₂-mediated signaling using human colon cancer cell lines, which predominantly express LPA₂. LPA₂ activated Akt and Erk1/2 in response to LPA. LPA mediated Akt activation was inhibited by pertussis toxin (PTX), whereas Erk1/2 activation was completely inhibited by a blocker of phospholipase C, U-73122. LPA also induced interleukin-8 (IL-8) synthesis in the colon cancer cells by primarily activating LPA₂ receptor. We also found that LPA₂ interacts with Na⁺/H⁺ exchanger regulatory factor 2 (NHERF2). Activation of Akt and Erk1/2 was significantly attenuated by silencing of NHERF2 expression by RNA interference, suggesting a pivotal role of NHERF2 in LPA₂-mediated signaling. We found that expression of LPA₂ was elevated, whereas expression of LPA₁ downregulated in several types of cancers, including ovarian and colon cancer. We conclude that LPA₂ is the major LPA receptor in colon cancer cells and cellular signals by LPA₂ are largely mediated through its ability to interact with NHERF2.

Na⁺/H⁺ exchanger regulatory factor 2

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