title: Beta-catenin, cancer, and G proteins: not just for frizzleds anymore.
abstract: 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 LPA(1), LPA(2), and LPA(3) (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 beta-catenin in a manner that depended on activation of Galpha(q) by LPA(2,3'), activation of phospholipase Cbeta, activation of a conventional protein kinase C, and phosphorylation and inhibition of glycogen synthase kinase 3-beta. The phosphorylation of beta-catenin by this kinase marks the protein for intracellular degradation; LPA suppresses this degradation and stimulates beta-catenin accumulation. Beta-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 beta-catenin provides a new dimension of knowledge linking lipid mediators to the dysregulation of beta-catenin signaling in cancer.
authors: Department of Pharmacology, School of Medicine, Health Sciences Center, SUNY-Stony Brook, Stony Brook, NY 11794-8651, USA. craig@pharm.sunysb.edu
authors: Craig C
authors: CC
authors: Malbon
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology; D051157:Frizzled Receptors / Q000737:chemistry / Q000502:physiology*; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D007448:Invertebrates / Q000502:physiology; D007527:Isoenzymes / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000502:physiology; D008246:Lysophospholipids / Q000494:pharmacology / Q000502:physiology*; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000737:chemistry / Q000502:physiology*; D009369:Neoplasms / Q000378:metabolism*; D054799:Phospholipase C beta; D011493:Protein Kinase C / Q000502:physiology; D049368:Receptors, Lysophosphatidic Acid / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000502:physiology; D014714:Vertebrates / Q000502:physiology; D051153:Wnt Proteins / Q000502:physiology; D051176:beta Catenin / Q000502:physiology*
chemical_list: D051157:Frizzled Receptors; D007527:Isoenzymes; D051821:Lymphoid Enhancer-Binding Factor 1; D008246:Lysophospholipids; D009363:Neoplasm Proteins; D049368:Receptors, Lysophosphatidic Acid; D051153:Wnt Proteins; D051176:beta Catenin; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D054799:Phospholipase C beta; D020962:Heterotrimeric GTP-Binding Proteins; C032881:lysophosphatidic acid