SPARC regulates TGF-beta1-dependent signaling in primary glomerular mesangial cells.
Secreted protein acidic and rich in cysteine (SPARC), a member of the family of matricellular proteins, regulates the interaction of cells with pleiotropic factors and proteins of the extracellular matrix (ECM). Although it has been appreciated that transforming growth factor beta 1 (TGF-beta1) induces SPARC and collagen type I, we have recently shown that SPARC regulates the expression of TGF-beta1 and collagen type I in renal mesangial cells via a TGF-beta1-dependent pathway, and have proposed a reciprocal, autocrine regulatory feedback loop between SPARC and TGF-beta1. Herein, we sought to determine how SPARC regulates TGF-beta1-dependent signal transduction. Our data indicate that SPARC modulates the TGF-beta1-dependent phosphorylation of Smad-2 in primary mesangial cells derived from wild-type and SPARC-null mice. We also show that SPARC regulates the levels and activation of the stress-activated c-jun-N-terminal kinase (JNK) in mesangial cells by augmentation of the stimulatory effects of TGF-beta1. Furthermore, we found that SPARC increases the levels and the activity of the transcription factor c-jun. These effects of SPARC on the TGF-beta1 signaling pathway appear to be mediated through an interaction with the TGF-beta1-receptor complex, but only in the presence of TGF-beta1 bound to its cognate type II receptor. That SPARC is directly involved in the regulation of the TGF-beta1 signaling cascade is consistent with the paradigm that matricellular proteins modulate interactions among cells, growth factors, and their respective receptors.
Francki
Aleksandar
A
Department of Vascular Biology, The Hope Heart Institute, Seattle, Washington 98104, USA.
McClure
Timothy D
TD
Brekken
Rolf A
RA
Motamed
Kouros
K
Murri
Carrie
C
Wang
Tongwen
T
Sage
E Helene
EH
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism; D004357:Drug Synergism; D005920:Glomerular Mesangium / Q000166:cytology / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D015676:Osteonectin / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D015676:Osteonectin; D016755:Proto-Oncogene Proteins c-jun; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016329:Sp1 Transcription Factor; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases