Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation
- Authors
- Dai, W., Bai, Y., Hebda, L., Zhong, X., Liu, J., Kao, J., and Duan, C.
- ID
- ZDB-PUB-140213-1
- Date
- 2014
- Source
- Cell death and differentiation 21(4): 568-81 (Journal)
- Registered Authors
- Duan, Cunming
- Keywords
- none
- MeSH Terms
-
- Phosphatidylinositol 3-Kinase/antagonists & inhibitors
- Phosphatidylinositol 3-Kinase/genetics
- Phosphatidylinositol 3-Kinase/metabolism
- Calcium/pharmacology*
- Signal Transduction/drug effects
- Zebrafish/growth & development
- Zebrafish/metabolism
- TRPV Cation Channels/antagonists & inhibitors
- TRPV Cation Channels/genetics
- TRPV Cation Channels/metabolism*
- Epithelial Cells/cytology
- Epithelial Cells/drug effects
- Epithelial Cells/metabolism*
- Receptor, IGF Type 1/antagonists & inhibitors
- Receptor, IGF Type 1/genetics
- Receptor, IGF Type 1/metabolism
- Cell Proliferation/drug effects
- Humans
- Caco-2 Cells
- Insulin-Like Growth Factor II/pharmacology
- Yolk Sac/cytology
- Zebrafish Proteins/antagonists & inhibitors
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- Proto-Oncogene Proteins c-akt/antagonists & inhibitors
- Proto-Oncogene Proteins c-akt/genetics
- Proto-Oncogene Proteins c-akt/metabolism
- Larva/cytology
- Animals
- Sodium-Potassium-Exchanging ATPase/metabolism
- Oligonucleotides, Antisense/metabolism
- Insulin-Like Growth Factor I/pharmacology
- PubMed
- 24336047 Full text @ Cell Death Differ.
Calcium deficiency causes abnormal colonic growth and increases colon cancer risk with poorly understood mechanisms. Here we elucidate a novel signaling mechanism underlying the Ca2+ deficiency-induced epithelial proliferation using a unique animal model. The zebrafish larval yolk sac skin contains a group of Ca2+-transporting epithelial cells known as ionocytes. Their number and density increases dramatically when acclimated to low >[Ca2+] environments. BrdU pulse-labeling experiments suggest that low [Ca2+] stimulates pre-existing ionocytes to re-enter the cell cycle. Low [Ca2+] 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 Ca2+-selective channel Trpv5/6. Inhibition or knockdown of Igfbp5a, IGF1 receptor, PI3K, and Akt attenuates low [Ca2+]-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 [Ca2+]. These increases are eliminated in the presence of an IGF1R inhibitor, suggesting that Trpv5/6 represses IGF1R-PI3K-Akt signaling under normal [Ca2+]. Intriguingly, blockade of Trpv5/6 activity inhibits the low [Ca2+]-induced activation of Akt. Mechanistic analyses reveal that the low [Ca2+]-induced IGF signaling is mediated through Trpv5/6-associated membrane depolarization. Low extracellular [Ca2+] 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 Ca2>+ deficiency.