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{beta}-Catenin, Cancer, and G Proteins: Not Just for Frizzleds Anymore

The lipid metabolite lysophosphatidic acid (LPA) mediates an impressive set of responses that includes morphogenesis, cell proliferation, cell survival, cell adhesion, and cell migration. LPA exerts its downstream signaling by binding to the LPA1, LPA2, and LPA3 (formerly Edg-2, -4, and -7) family of seven-transmembrane, segmented, heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors. LPA actions of therapeutic interest include effects on wound healing, atherogenesis, thrombogenesis, and, of course, cancer. LPA has been implicated in the progression of human breast, ovarian, prostate, head and neck, and colon malignancies. In view of these earlier observations, a recent report that LPA stimulates the proliferation of colon cancer–derived cell lines was greeted with great anticipation for its possible contribution to the unraveling of details of cancer signaling downstream of LPA. LPA was shown to stimulate nuclear accumulation of β-catenin in a manner that depended on activation of Gαq by LPA2,3, activation of phospholipase Cβ, activation of a conventional protein kinase C, and phosphorylation and inhibition of glycogen synthase kinase 3-β. The phosphorylation of β-catenin by this kinase marks the protein for intracellular degradation; LPA suppresses this degradation and stimulates β-catenin accumulation. β-catenin is a pivotal molecule in the control of cell cycle progression and gene expression, activating both processes in combination with lymphoid-enhancing factor/T cell–factor–sensitive transcription and inhibiting both processes in combination with FOXO transcription factors. The ability of LPA to increase the cytoplasmic and nuclear accumulation of β-catenin provides a new dimension of knowledge linking lipid mediators to the dysregulation of β-catenin signaling in cancer.

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Classifications


Resource Type: Diagram, Illustration, Journal article/Issue, Review
Audience Level: Undergraduate upper division 15-16, Graduate, Professional (degree program)

Author and Copyright


Authors and Editors: Craig C. Malbon of Department of Pharmacology, School of Medicine Health Sciences Center SUNY-Stony Brook
Publisher: American Association for the Advancement of Science
Format: application/pdf, image/gif, image/jpeg, text/html
Copyright and other restrictions: Yes
Cost: Yes

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