MicroRNA-21 targets Sprouty2 and promotes cellular outgrowths.
The posttranscriptional regulator, microRNA-21 (miR-21), is up-regulated in many forms of cancer, as well as during cardiac hypertrophic growth. To understand its role, we overexpressed it in cardiocytes where it revealed a unique type of cell-to-cell "linker" in the form of long slender outgrowths and branches. We subsequently confirmed that miR-21 directly targets and down-regulates the expression of Sprouty2 (SPRY2), an inhibitor of branching morphogenesis and neurite outgrowths. We found that beta-adrenergic receptor (betaAR) stimulation induces up-regulation of miR-21 and down-regulation of SPRY2 and is, likewise, associated with connecting cell branches. Knockdown of SPRY2 reproduced the branching morphology in cardiocytes, and vice versa, knockdown of miR-21 using a specific 'miRNA eraser' or overexpression of SPRY2 inhibited betaAR-induced cellular outgrowths. These structures enclose sarcomeres and connect adjacent cardiocytes through functional gap junctions. To determine how this aspect of miR-21 function translates in cancer cells, we knocked it down in colon cancer SW480 cells. This resulted in disappearance of their microvillus-like protrusions accompanied by SPRY2-dependent inhibition of cell migration. Thus, we propose that an increase in miR-21 enhances the formation of various types of cellular protrusions through directly targeting and down-regulating SPRY2.
Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
Danish
D
Sayed
Shweta
S
Rane
Jacqueline
J
Lypowy
Minzhen
M
He
Ieng-Yi
IY
Chen
Himanshu
H
Vashistha
Lin
L
Yan
Ashwani
A
Malhotra
Dorothy
D
Vatner
Maha
M
Abdellatif
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002450:Cell Communication; D002465:Cell Movement; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D017629:Gap Junctions; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D012323:RNA Processing, Post-Transcriptional; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013347:Subcellular Fractions
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C531950:MIRN21 microRNA, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; D011943:Receptors, Adrenergic, beta; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse