Disease relevance of Tgfbr1

• Epidermal TGF-beta type I and II receptor (T beta RI and T beta RII) levels were examined in control and transgenic mice during induction of hyperplasia by TPA [1].
• Our results identify the first inactivating mutation in TbetaR-I gene in a human lymphoma that renders it insensitive to growth inhibition by TGF-beta [2].
• The co-administration of a p38 MAPK inhibitor and an ALK5 inhibitor may have potential applications in the treatment of renal fibrosis [3].
• In contrast, none of the mice receiving transfectants of TbetaRI formed bladder tumors or metastases [4].
• Our results suggest that TGF-beta plays a pivotal role in the pathologic processes in retinal gliosis, and that the systemically expressed soluble TGF receptor by gene delivery may thus have a potential therapeutic value by inhibiting excessive retinal gliosis in various ocular diseases [5].

High impact information on Tgfbr1

• ALK-5 has been shown to be a functional TGF-beta type I receptor [6].
• Our results suggest that TGF-beta regulates the activation state of the endothelium via a fine balance between ALK5 and ALK1 signalling [7].
• Endothelial cells derived from TbetaRI-deficient embryos show enhanced cell proliferation, improper migratory behavior and impaired fibronectin production in vitro, defects that are associated with the vascular defects seen in vivo [8].
• However, despite obvious anemia in the TbetaRI(-/-) yolk sacs, clonogenic assays on yolk sac-derived hematopoietic precursors in vitro revealed that TbetaRI(-/-) mice exhibit normal hematopoietic potential compared with wild-type and heterozygous siblings [8].
• However, induced T beta RI null mice show normal in vivo hematopoiesis with normal numbers and differentiation ability of hematopoietic progenitor cells [9].

Biological context of Tgfbr1

• Overall, the results indicate a key role for a tumour suppressor gene(s) encoded in an approximately 3 cM segment on proximal chromosome 4 and provide an experimental basis for the further investigation of the functional role of candidate genes which include Pax5 and Tgfbr1 [10].
• Transgenic mice expressing an active mutant of Alk5 in the mammary gland (MMTV-Alk5(T204D)) exhibited reduced apoptosis in terminal endbuds and during postlactational involution [11].
• The Alk5(lacZ) mice will be a valuable resource in identifying the in vivo cellular targets of TGF-beta family signals mediated by Alk5, both during embryonic development as well as in diverse pathological conditions [12].
• Furthermore HSCs from T beta RI null mice exhibit a normal cell cycle distribution and do not differ in their ability long term to repopulate primary and secondary recipient mice following bone marrow transplantation [9].
• Hybridization of a radiolabeled fragment internal to the deletion was detected in the genomes of TGF-beta-responsive cells, but not in JK cells, indicating that they contain no wild-type TbetaR-I gene [2].

Anatomical context of Tgfbr1

• With RT-PCR, expression of the signaling TGF-beta receptors (types II and ALK-5) was shown to be absent in isolated germ layers of 6.0-7.5 days postcoitum (dpc) embryos, whereas the type III receptor and Tsk 7L were differentially expressed at these stages [13].
• In addition, although Alk5-null embryos exhibit a defect in the formation of vascular smooth muscle layers, the lumens of blood vessels are generated properly, which stands in contrast to the severe dilation of the vascular lumens in Alk1-null mice [12].
• In blood vessels, contrasting to predominant Alk1 expression in arterial endothelium, Alk5 expression was localized in the medial and adventitial layers of blood vessels, but was undetectable in the intimal layer [12].
• Overall, a high level of Alk5 expression was found in perichondria, periostea, and the mesenchymal layers underlying epithelia in the kidney, lung, and gallbladder [12].
• BACKGROUND: In endothelial cells (EC), transforming growth factor-beta (TGF-beta) can bind to and transduce signals through ALK1 and ALK5 [14].

Associations of Tgfbr1 with chemical compounds

• Whereas T beta RI levels remained relatively constant, T beta RII expression was strongly induced in TPA-treated skins, prior to the induction of the growth inhibitory response to TGF-beta 1, and its level of expression correlated with growth sensitivity to TGF-beta 1 in vivo and in vitro [1].
• Reverse transcriptase-polymerase chain reaction (RT-PCR) and sequencing of JK cell TbetaR-I cDNA clones identified a deletion that spanned the last 178 bp of exon 1, including the initiating methionine [2].
• Utilizing pSmad3(-3) as a substrate, we have shown that novel pyrazole compounds are potent inhibitors of TbetaRI kinase with K(i) value as low as 15 nM [15].
• METHODS: TbetaRI null and control bone marrow chimeras were subjected to repeated treatments with the cell cycle-specific cytotoxic drug 5-fluorouracil (5-FU) and surviving HSCs were assayed by competitive transplantation experiments [16].

Physical interactions of Tgfbr1

• Transforming growth factor-beta (TGFbeta) isoforms initiate signaling by assembling a heterotetrameric complex of paired type I (TbetaRI) and type II (TbetaRII) receptors on the cell surface [17].
• Here, we show that the extracellular domain of TbetaRI (TbetaRI-ED) binds in vitro with high affinity to complexes of the extracellular domain of TbetaRII (TbetaRII-ED) and TGFbetas 1 or 3, but not to either ligand or receptor alone [17].

Enzymatic interactions of Tgfbr1

• Several studies have shown that TbetaR-II acts as a primary receptor, binding TGF-beta and phosphorylating TbetaR-I, whose kinase activity then propagates the signals [18].

Regulatory relationships of Tgfbr1

• These results suggest that TGF beta-1 regulates two key dentin proteins involved in matrix mineralization most likely mediated through the type I ALK5 receptor and transduced by Smads 2, 3, and 4 [19].
• We here demonstrated that TGF betas and T beta R-I are expressed in hair follicle epithelium and have found a positive reactivity for LTBP and T beta R-I in ++sebocytes [20].

Other interactions of Tgfbr1

• Growth differentiation factor 11 signals through the transforming growth factor-beta receptor ALK5 to regionalize the anterior-posterior axis [21].
• Alk5 mutant embryos showed malformations in anterior-posterior patterning, including the lack of expression of the posterior determinant Hoxc10, that resemble defects found in Gdf11-null mutants [21].
• The expression of TbetaR-III was temporo-spatially restricted to the MEE during palatal fusion, while the expression of TbetaR-I was primarily localized in all palatal epithelia, consistent with the expression patterns of TbetaR-II and TGF-beta3 (Cui et al., 1998) [22].
• ALK-3 and ALK-5 mRNAs first decreased on day 14 and increased again on day 21 [23].
• The TGF-(beta) type I receptor (ALK-5) and its effector Smad proteins mediate the epithelial to mesenchymal transition [24].

Analytical, diagnostic and therapeutic context of Tgfbr1

• To investigate the role of TGF-beta type III receptor (TbetaR-III) in MEE transformation, we examined the expression pattern of TbetaR-III in the developing palate from E12 to E15 mice in vivo and in vitro by immunohistochemistry and compared the expression pattern to that of type I receptor (TbetaR-I) [22].
• To define the function of TGF-beta more precisely, we inactivated the TGF-beta type I receptor (TbetaRI) gene by gene targeting [8].
• PCR primers that flanked the deleted TbetaR-I region amplified a single band from JK cell genomic DNA that lacked the last 178 bp of exon 1 and all of the approximately 5 kb of intron 1 [2].
• Antibody-mediated immunofluorescence co-patching of epitope-tagged receptors provides the first evidence in live cells that TbetaRI [25].
• Velocity centrifugation of endogenous receptors suggests that ligand-bound TbetaRI and TbetaRII form a heteromeric complex that is most likely a heterotetramer [25].

References