TGF-beta-induced Ca(2+) influx involves the type III IP(3) receptor and regulates actin cytoskeleton.
Ca(2+) influx has been postulated to modulate the signaling pathway of transforming growth factor-beta (TGF-beta); however, the underlying mechanism and functional significance of TGF-beta-induced stimulation of Ca(2+) influx are unclear. We show here that TGF-beta stimulates Ca(2+) influx in mesangial cells without Ca(2+) release. The influx of Ca(2+) is prevented by pharmacological inhibitors of inositol 1,4,5-trisphosphate receptors (IP(3)R) as well as specific antibodies to type III IP(3)R (IP(3)RIII) but not to type I IP(3)R (IP(3)RI). TGF-beta enhances plasma membrane localization of IP(3)RIII, whereas the sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase (SERCA) preferentially translocates to the nucleus. Untreated mesangial cells exhibit actin filamentous protrusions on the cell surface, and treatment with TGF-beta dramatically reduces this pattern. The alterations in the actin cytoskeleton by TGF-beta are dependent on TGF-beta-induced Ca(2+) influx. These studies identify a novel pathway by which TGF-beta regulates Ca(2+) influx and induces cytoskeletal alterations.
McGowan
Tracy A
TA
Dorrance Hamilton Laboratory, Division of Nephrology, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Madesh
Muniswamy
M
Zhu
Yanqing
Y
Wang
Lewei
L
Russo
Mark
M
Deelman
Leo
L
Henning
Rob
R
Joseph
Suresh
S
Hajnoczky
Gyorgy
G
Sharma
Kumar
K
D000199:Actins / Q000032:analysis / Q000737:chemistry; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000032:analysis / Q000276:immunology / Q000502:physiology*; D002132:Calcium Radioisotopes / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry; D003599:Cytoskeleton / Q000737:chemistry / Q000187:drug effects / Q000648:ultrastructure*; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000648:ultrastructure; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors; D051379:Mice; D016253:Microscopy, Immunoelectron; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000276:immunology / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015398:Signal Transduction; D013539:Simian virus 40; D019284:Thapsigargin / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology* / Q000502:physiology
D000199:Actins; D000906:Antibodies; D015220:Calcium Channels; D002132:Calcium Radioisotopes; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D016212:Transforming Growth Factor beta; D019284:Thapsigargin; D015544:Inositol 1,4,5-Trisphosphate; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium