Imbalanced expression of the type I TGF-beta receptors ALK-1 and ALK-5 in pulmonary fibrosis

Transforming growth factor-beta 1 (TGF-beta 1) is strongly expressed during embryogenesis and in sites undergoing intense development and morphogenesis. Two receptor serine/threonine kinases (types I and II) have been identified as signal-transducing TGF-beta receptors. This study was undertaken to further explore the role of the distinct TGF-beta receptors during kidney development. The species-specific sequence information for the two T beta R-I, namely, activin receptor-like kinase-5 (ALK-5) and Tsk7L, in the rat was sought. Two full-length T beta R-I cDNAs were cloned from a neonatal rat kidney and lung libraries, and sequencing revealed that they were the rat homologs of human ALK-5 and murine Tsk7L. Both types I and II TGF-beta receptors are expressed in the kidney as determined by Northern blot analysis. T beta R-II mRNA abundance was significantly greater in the neonatal rat kidney compared with the adult rat kidney. Similarly, ALK-5 mRNA was more highly expressed in the fetal and neonatal rat kidney than the adult rat kidney. In contrast, there was no significant difference in Tsk7L mRNA abundance among the fetal, neonatal, and adult rat kidney. Thus, based on these findings, both T beta R-II and ALK-5 are developmentally regulated in the kidney. Increased expression of T beta R-II and ALK-5 proteins in the developing kidney was confirmed by immunohistochemistry. Interestingly, the two TGF-beta receptors did not entirely colocalize, raising the intriguing possibility that other TGF-beta signaling receptors may be involved.

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TGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells

Journal of Cell Science ◽

10.1242/jcs.112.24.4557 ◽

1999 ◽

Vol 112 (24) ◽

pp. 4557-4568 ◽

Cited By ~ 21

Author(s):

E. Piek ◽

A. Moustakas ◽

A. Kurisaki ◽

C.H. Heldin ◽

P. ten Dijke

Keyword(s):

Transforming Growth Factor ◽

Activin A ◽

Nuclear Accumulation ◽

Type I ◽

Beta Catenin ◽

Tgf Beta ◽

Mesenchymal Transition ◽

Smad Proteins ◽

Mesenchymal Transformation ◽

Alk 5

The capacities of different transforming growth factor-(beta) (TGF-(beta)) superfamily members to drive epithelial to mesenchymal transdifferentiation of the murine mammary epithelial cell line NMuMG were investigated. TGF-(beta)1, but not activin A or osteogenic protein-1 (OP-1)/bone morphogenetic protein-7 (BMP-7), was able to induce morphological transformation of NMuMG cells as shown by reorganisation of the actin cytoskeleton and relocalisation/downregulation of E-cadherin and (beta)-catenin, an effect that was abrogated by the more general serine/threonine kinase and protein kinase C inhibitor, staurosporine. TGF-(beta)1 bound to TGF-(beta) type I receptor (T(beta)R-I)/ALK-5 and T(beta)R-II, but not to activin type I receptor (ActR-I)/ALK-2. Activin A bound to ActR-IB/ALK-4 and ActR-II, and BMP-7 bound to ActR-I/ALK-2, BMP type I receptor (BMPR-I)/ALK-3, ActR-II and BMPR-II. TGF-(beta)1 and BMP-7 activated the Smad-binding element (SBE)(4) promoter with equal potency, whereas activin A had no effect. Transfection of constitutively active (CA)-ALK-4 activated the 3TP promoter to the same extent as TGF-(beta)1 and CA-ALK-5 indicating that activin signalling downstream of type I receptors was functional in NMuMG cells. In agreement with this, activin A induced low levels of plasminogen activator inhibitor I expression compared to the high induction by TGF-(beta)1. In contrast to activin A and BMP-7, TGF-(beta)1 strongly induced Smad2 phosphorylation. Consistent with these findings, TGF-(beta)1 induced the nuclear accumulation of Smad2 and/or Smad3. In addition, NMuMG cells transiently infected with adenoviral vectors expressing high level CA-ALK-5 exhibited full transdifferentiation. On the other hand, infections with low level CA-ALK-5, which alone did not result in transdifferentiation, together with Smad2 and Smad4, or with Smad3 and Smad4 led to transdifferentiation. In conclusion, TGF-(beta)1 signals potently and passes the activation threshold to evoke NMuMG cell transdifferentiation. The TGF-(beta) type I receptor (ALK-5) and its effector Smad proteins mediate the epithelial to mesenchymal transition. Activin A does not induce mesenchymal transformation, presumably because the number of activin receptors is limited, while BMP-7-initiated signalling cannot mediate transdifferentiation.

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Expression of TGF-beta receptors type I and II in human glomerulonephritis

Nephrology Dialysis Transplantation ◽

10.1093/ndt/13.2.277 ◽

1998 ◽

Vol 13 (2) ◽

pp. 277-282 ◽

Cited By ~ 1

Author(s):

A Muda

Keyword(s):

Type I ◽

Tgf Beta ◽

Beta Receptors

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The Src Family Kinase Inhibitors PP2 and PP1 Block TGF-Beta1-Mediated Cellular Responses by Direct and Differential Inhibition of Type I and Type II TGF-Beta Receptors

Current Cancer Drug Targets ◽

10.2174/156800911795538075 ◽

2011 ◽

Vol 11 (4) ◽

pp. 524-535 ◽

Cited By ~ 29

Author(s):

H. Ungefroren ◽

S. Sebens ◽

S. Groth ◽

F. Gieseler ◽

F. Fandrich

Keyword(s):

Kinase Inhibitors ◽

Cellular Responses ◽

Type I ◽

Type Ii ◽

Differential Inhibition ◽

Tgf Beta ◽

Src Family Kinase ◽

Beta Receptors

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Expression of types I, II, and III TGF-beta receptors in human glomerulonephritis.

Journal of the American Society of Nephrology ◽

10.1681/asn.v9122253 ◽

1998 ◽

Vol 9 (12) ◽

pp. 2253-2261

Author(s):

T Yamamoto ◽

T Watanabe ◽

N Ikegaya ◽

Y Fujigaki ◽

K Matsui ◽

...

Keyword(s):

Endothelial Cells ◽

Lupus Nephritis ◽

Iga Nephropathy ◽

Membranoproliferative Glomerulonephritis ◽

Type I ◽

Tgf Beta ◽

Matrix Deposition ◽

Peritubular Capillaries ◽

Tubulointerstitial Lesions ◽

Beta Receptors

Protein and mRNA expression of transforming growth factor-beta (TGF-beta) receptor type I (TbetaRI), type II (TbetaRII), and type III (TbetaRIII) were studied in serial sections of kidney samples obtained from patients with glomerulonephritis. In minimal change disease, weak expression of TbetaRI and TbetaRII was observed mainly in glomerular endothelial cells, peritubular capillaries, and interstitial arteriolar endothelial cells, whereas TbetaRIII expression was found mainly in the interstitium. Expression of all three TGF-beta receptors (TbetaR) was increased remarkably in glomerular and Bowman's capsular cells comprising the tuft adhesions to Bowman's capsules in glomerulonephritis with increased matrix accumulation, including IgA nephropathy, lupus nephritis, focal and segmental glomerulosclerosis, myeloperoxidase-antineutrophil cytoplasmic antibody-associated crescentic glomerulonephritis, and membranoproliferative glomerulonephritis. Increased expression of the three TbetaR was also seen in glomerular epithelial cells in the vicinity of glomerulosclerotic lesions, in crescent cells, and in some tubules and infiltrative mononuclear cells found in the periglomerular and tubulointerstitial lesions with increased matrix deposition. In contrast, no remarkable TbetaRII expression was noted in mesangial proliferative lesions in IgA nephropathy, lupus nephritis, and membranoproliferative glomerulonephritis. These data suggest that distinctive modulation of TbetaR expression may be involved in the development of adhesive, sclerotic, and proliferative renal lesions in human glomerulonephritis.

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