Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

被引:75
作者
Dai, W. [1 ]
Bai, Y. [1 ]
Hebda, L. [1 ]
Zhong, X. [1 ,2 ]
Liu, J. [1 ]
Kao, J. [1 ]
Duan, C. [1 ]
机构
[1] Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA
[2] Cent China Normal Univ, Coll Life Sci, Hubei Key Lab Genet Regulat & Integrat Biol, Wuhan 430079, Peoples R China
基金
美国国家科学基金会;
关键词
transient receptor potential vanilloid; insulin-like growth factor binding protein 5; zebrafish; colon cancer cell; epithelial growth; membrane depolarization; IGF-BINDING; VITAMIN-D; SENSING RECEPTOR; PORE PROPERTIES; DAIRY-PRODUCTS; COLON-CANCER; IN-VIVO; GROWTH; EXPRESSION; SURVIVAL;
D O I
10.1038/cdd.2013.177
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 Ca-2+ 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.
引用
收藏
页码:568 / 581
页数:14
相关论文
共 55 条
[31]   Evidence that IGF-binding protein-5 functions as a growth factor [J].
Miyakoshi, N ;
Richman, C ;
Kasukawa, Y ;
Linkhart, TA ;
Baylink, DJ ;
Mohan, S .
JOURNAL OF CLINICAL INVESTIGATION, 2001, 107 (01) :73-81
[32]  
Nemeth EF, 2001, J PHARMACOL EXP THER, V299, P323
[33]   Whole-cell and single channel monovalent cation currents through the novel rabbit epithelial Ca2+ channel ECaC [J].
Nilius, B ;
Vennekens, R ;
Prenen, J ;
Hoenderop, JGJ ;
Bindels, RJM ;
Droogmans, G .
JOURNAL OF PHYSIOLOGY-LONDON, 2000, 527 (02) :239-248
[34]   Epithelial Ca2+ channel expression and Ca2+ uptake in developing zebrafish [J].
Pan, TC ;
Liao, BK ;
Huang, CJ ;
Lin, LY ;
Hwang, PP .
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 2005, 289 (04) :R1202-R1211
[35]  
PERRY SF, 1985, J EXP BIOL, V116, P411
[36]   Vitamin D and calcium deficits predispose for multiple chronic diseases [J].
Peterlik, M ;
Cross, HS .
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, 2005, 35 (05) :290-304
[37]   IGFs stimulate zebrafish cell proliferation by activating MAP kinase and PI3-kinase-signaling pathways [J].
Pozios, KC ;
Ding, J ;
Degger, B ;
Upton, Z ;
Duan, C .
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 2001, 280 (04) :R1230-R1239
[38]   IGFBP-5 regulates muscle cell differentiation by binding to IGF-II and switching on the IGF-II auto-regulation loop [J].
Ren, Hongxia ;
Yin, Ping ;
Duan, Cunming .
JOURNAL OF CELL BIOLOGY, 2008, 182 (05) :979-991
[39]   Insulin-like growth factor signaling regulates zebrafish embryonic growth and development by promoting cell survival and cell cycle progression [J].
Schlueter, P. J. ;
Peng, G. ;
Westerfield, M. ;
Duan, C. .
CELL DEATH AND DIFFERENTIATION, 2007, 14 (06) :1095-1105
[40]   Activation of the Ca2+-sensing receptor stimulates the activity of the epithelial Ca2+ channel TRPV5 [J].
Topala, Catalin N. ;
Schoeber, Joost P. H. ;
Searchfield, Lydia E. ;
Riccardi, Daniela ;
Hoenderop, Joost G. J. ;
Bindels, Rene J. M. .
CELL CALCIUM, 2009, 45 (04) :331-339