title: Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation.
abstract: Calcium deficiency causes abnormal colonic growth and increases colon cancer risk with poorly understood mechanisms. Here we elucidate a novel signaling mechanism underlying the Ca(2+) deficiency-induced epithelial proliferation using a unique animal model. The zebrafish larval yolk sac skin contains a group of Ca(2+)-transporting epithelial cells known as ionocytes. Their number and density increases dramatically when acclimated to low [Ca(2+)] environments. BrdU pulse-labeling experiments suggest that low [Ca(2+)] stimulates pre-existing ionocytes to re-enter the cell cycle. Low [Ca(2+)] treatment results in a robust and sustained activation of IGF1R-PI3K-Akt signaling in these cells exclusively. These ionocytes specifically express Igfbp5a, a high-affinity and specific binding protein for insulin-like growth factors (IGFs) and the Ca(2+)-selective channel Trpv5/6. Inhibition or knockdown of Igfbp5a, IGF1 receptor, PI3K, and Akt attenuates low [Ca(2+)]-induced ionocyte proliferation. The role of Trpv5/6 was investigated using a genetic mutant, targeted knockdown, and pharmacological inhibition. Loss-of-Trpv5/6 function or expression results in elevated pAkt levels and increased ionocyte proliferation under normal [Ca(2+)]. These increases are eliminated in the presence of an IGF1R inhibitor, suggesting that Trpv5/6 represses IGF1R-PI3K-Akt signaling under normal [Ca(2+)]. Intriguingly, blockade of Trpv5/6 activity inhibits the low [Ca(2+)]-induced activation of Akt. Mechanistic analyses reveal that the low [Ca(2+)]-induced IGF signaling is mediated through Trpv5/6-associated membrane depolarization. Low extracellular [Ca(2+)] results in a similar amplification of IGF-induced PI3K-PDK1-Akt signaling in human colon cancer cells in a TRPV6-dependent manner. These results uncover a novel and evolutionarily conserved signaling mechanism that contributes to the abnormal epithelial proliferation associated with Ca(2+) deficiency.
authors: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: W
authors: W
authors: Dai
authors: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Y
authors: Y
authors: Bai
authors: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: L
authors: L
authors: Hebda
authors: 1] Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA [2] Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University, Wuhan 430079, China.
authors: X
authors: X
authors: Zhong
authors: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: J
authors: J
authors: Liu
authors: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: J
authors: J
authors: Kao
authors: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: C
authors: C
authors: Duan
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002118:Calcium / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D007814:Larva / Q000166:cytology; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015017:Yolk Sac / Q000166:cytology; D015027:Zebrafish / Q000254:growth & development / Q000378:metabolism; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016376:Oligonucleotides, Antisense; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050916:TRPV Cation Channels; D029961:Zebrafish Proteins; C505134:trpv6 protein, zebrafish; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D058539:Phosphatidylinositol 3-Kinase; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium