ALK5

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Medline Suchterm/ Synonyme (alk5 OR alk-5 OR activin-like kinase 5) sowie alle Variationen von (TGF beta type I receptor OR transforming growth factor beta type I receptor)
Was ist das Rezeptorkomponente für TGF-beta, hat Serin/Threonin-Kinaseaktivität, aktiviert smad2/smad3;smad7, hierdurch Signaltransduktion, beeinflußt Gene mit der Folge Antiproliferation, Fibrose, Matrixproduktion, Zelldifferenzierung epithelialer Zellen zum mesenchyalen Charakter hin, Immunsuppression. Wichtig für Angiogenese und entwicklungsbiologische Vorgänge sowie Wundheilung.
Struktur [1]
Physiologie Signaltransduktion: [2]

Angiogenese: [3][4][5][6][7]

Fibrose/Myofibroblast/Epithelio-mesenchymale Transdifferenzierung: [8][9][10][11][12]

Entwicklungsbiologie: [13][14][15][16][17][18]

Knockout [19][20]
Transgen
Mutation [21][22]
Polymorphismus
Genexpression
Inhibitoren Z.B. SD208, SM16, SB431542, SB505124: [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]
Agonisten TGF-beta, GDF11 [39], GDF9[40]

1 Bibliographie[Bearbeiten]

  1. TGFbeta-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGFbeta switch. EMBO J 28(2):88-98 (2009) PMID 19096363
  2. Gene expression profiling demonstrates that TGF-beta1 signals exclusively through receptor complexes involving Alk5 and identifies targets of TGF-beta signaling. Physiol Genomics 21(3):396-403 (2005) PMID 15769904
  3. Activin-like kinase 5 (ALK5) mediates abnormal proliferation of vascular smooth muscle cells from patients with familial pulmonary arterial hypertension and is involved in the progression of experimental pulmonary arterial hypertension induced by monocrotaline. Am J Pathol 174(2):380-9 (2009) PMID 19116361
  4. Transforming growth factor-beta1 protects against pulmonary artery endothelial cell apoptosis via ALK5. Am J Physiol Lung Cell Mol Physiol 295(1):L123-33 (2008) PMID 18456797
  5. Nonoverlapping expression patterns of ALK1 and ALK5 reveal distinct roles of each receptor in vascular development. Lab Invest 86(2):116-29 (2006) PMID 16344855
  6. TGFbeta1 induces vasculogenesis and inhibits angiogenic sprouting in an embryonic stem cell differentiation model: respective contribution of ALK1 and ALK5. Stem Cells 24(11):2420-7 (2006) PMID 17071858
  7. TGF-beta inhibits vascular sprouting through TGF-beta type I receptor in the mouse embryonic aorta. Tohoku J Exp Med 218(1):63-71 (2009) PMID 19398875
  8. Matrix contraction by dermal fibroblasts requires transforming growth factor-beta/activin-linked kinase 5, heparan sulfate-containing proteoglycans, and MEK/ERK: insights into pathological scarring in chronic fibrotic disease. Am J Pathol 167(6):1699-711 (2005) PMID 16314481
  9. Enhanced expression of transforming growth factor-beta type I and type II receptors in wound granulation tissue and hypertrophic scar. Am J Pathol 152(2):485-93 (1998) PMID 9466575
  10. Contribution of activin receptor-like kinase 5 (transforming growth factor beta receptor type I) signaling to the fibrotic phenotype of scleroderma fibroblasts. Arthritis Rheum 54(4):1309-16 (2006) PMID 16575856
  11. TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J Cell Biol 127(6 Pt 2):2021-36 (1994) PMID 7806579
  12. TGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells. J Cell Sci 112 ( Pt 24)():4557-68 (1999) PMID 10574705
  13. Signaling via the Tgf-beta type I receptor Alk5 in heart development. Dev Biol 322(1):208-18 (2008) PMID 18718461
  14. Endoglin and Alk5 regulate epithelial-mesenchymal transformation during cardiac valve formation. Dev Biol 304(1):420-32 (2007) PMID 17250821
  15. Epithelial and ectomesenchymal role of the type I TGF-beta receptor ALK5 during facial morphogenesis and palatal fusion. Dev Biol 296(2):298-314 (2006) PMID 16806156
  16. Transforming growth factor-beta induces loss of epithelial character and smooth muscle cell differentiation in epicardial cells. Dev Dyn 235(1):82-93 (2006) PMID 16258965
  17. Transforming growth factor-beta stimulates epithelial-mesenchymal transformation in the proepicardium. Dev Dyn 235(1):50-9 (2006) PMID 16245329
  18. Signaling through Tgf-beta type I receptor Alk5 is required for upper lip fusion. Mech Dev 125(9-10):874-82 (2008) PMID 18586087
  19. Defective ALK5 signaling in the neural crest leads to increased postmigratory neural crest cell apoptosis and severe outflow tract defects. BMC Dev Biol 6():51 (2006) PMID 17078885
  20. Functional analysis of the TGFbeta receptor/Smad pathway through gene ablation in mice. Int J Dev Biol 44(3):253-65 (2000) PMID 10853822
  21. Cancer-associated transforming growth factor beta type II receptor gene mutant causes activation of bone morphogenic protein-Smads and invasive phenotype. Cancer Res 68(6):1656-66 (2008) PMID 18339844
  22. Disease-associated mutations in conserved residues of ALK-1 kinase domain. Eur J Hum Genet 11(4):279-87 (2003) PMID 12700602
  23. Progressive transforming growth factor beta1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor. Am J Respir Crit Care Med 171(8):889-98 (2005) PMID 15563636
  24. SB-431542, a transforming growth factor beta inhibitor, impairs Trypanosoma cruzi infection in cardiomyocytes and parasite cycle completion. Antimicrob Agents Chemother 51(8):2905-10 (2007) PMID 17526757
  25. SM16, an orally active TGF-beta type I receptor inhibitor prevents myofibroblast induction and vascular fibrosis in the rat carotid injury model. Arterioscler Thromb Vasc Biol 28(4):665-71 (2008) PMID 18202322
  26. Selective inhibition of activin receptor-like kinase 5 signaling blocks profibrotic transforming growth factor beta responses in skin fibroblasts. Arthritis Rheum 50(12):4008-21 (2004) PMID 15593186
  27. Inhibition of the TGF-beta receptor I kinase promotes hematopoiesis in MDS. Blood 112(8):3434-43 (2008) PMID 18474728
  28. Inhibition of TGF-beta signaling by an ALK5 inhibitor protects rats from dimethylnitrosamine-induced liver fibrosis. Br J Pharmacol 145(2):166-77 (2005) PMID 15723089
  29. A novel small-molecule inhibitor of transforming growth factor beta type I receptor kinase (SM16) inhibits murine mesothelioma tumor growth in vivo and prevents tumor recurrence after surgical resection. Cancer Res 67(5):2351-9 (2007) PMID 17332368
  30. SB-431542 and Gleevec inhibit transforming growth factor-beta-induced proliferation of human osteosarcoma cells. Cancer Res 63(22):7791-8 (2003) PMID 14633705
  31. Tumor-specific efficacy of transforming growth factor-beta RI inhibition in Eker rats. Clin Cancer Res 13(10):3087-99 (2007) PMID 17505012
  32. TGFbeta induces SIK to negatively regulate type I receptor kinase signaling. J Cell Biol 182(4):655-62 (2008) PMID 18725536
  33. Intracellular TGF-beta receptor blockade abrogates Smad-dependent fibroblast activation in vitro and in vivo. J Invest Dermatol 126(8):1733-44 (2006) PMID 16741519
  34. Inhibition of gene markers of fibrosis with a novel inhibitor of transforming growth factor-beta type I receptor kinase in puromycin-induced nephritis. J Pharmacol Exp Ther 313(3):943-51 (2005) PMID 15769863
  35. SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7. Mol Pharmacol 65(3):744-52 (2004) PMID 14978253
  36. SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol 62(1):65-74 (2002) PMID 12065756
  37. Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542. Mol Pharmacol 62(1):58-64 (2002) PMID 12065755
  38. Inhibitory effect of blocking TGF-beta/Smad signal on injury-induced fibrosis of corneal endothelium. Mol Vis 14():2272-81 (2008) PMID 19081766
  39. Growth differentiation factor 11 signals through the transforming growth factor-beta receptor ALK5 to regionalize the anterior-posterior axis. EMBO Rep 7(8):831-7 (2006) PMID 16845371
  40. Growth differentiation factor-9 signaling is mediated by the type I receptor, activin receptor-like kinase 5. Mol Endocrinol 18(3):653-65 (2004) PMID 14684852

2 Andere Lexika[Bearbeiten]