Disease relevance of Acvrl1

• Expression of ALK1 in blood vessels and mutations of the ALK1 gene in human type II hereditary hemorrhagic telangiectasia patients suggest that ALK1 may have an important role during vascular development [1].
• Arteriovenous malformations in mice lacking activin receptor-like kinase-1 [2].
• The transforming growth factor beta (TGF-beta) receptor, ALK-1, is expressed specifically on endothelial cells and is essential for angiogenesis, as demonstrated by its targeted deletion in mice and its mutation in the human disease hereditary hemorrhagic telangiectasia [3].
• The oncogenic fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) induces two distinct malignant phenotypes in a murine retroviral transplantation model [4].
• We have recently shown that some neuroblastoma cell lines, such as NB-39-nu cells, express a protein complex of hyperphosphorylated ShcC and anaplastic lymphoma kinase (ALK), which is self-activated by gene amplification [5].
• Alk1-conditional deletion resulted in severe vascular malformations mimicking all pathologic features of HHT [6].

High impact information on Acvrl1

• At the earliest stage of vascular development, mice lacking Acvrl1 develop large shunts between arteries and veins, downregulate arterial Efnb2 and fail to confine intravascular haematopoiesis to arteries [2].
• However, the function of endoglin in TGF-beta/ALK signalling has remained unclear [7].
• Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction [7].
• Consistent with this hypothesis, we demonstrate that ALK1 in endothelial cells binds to TGF-beta1 and TbetaR-II [1].
• Genetic studies in mouse and zebrafish have established the importance of activin receptor-like kinase 1 (ALK1) in formation and remodeling of blood vessels [8].

Chemical compound and disease context of Acvrl1

• Anaplastic Lymphoma Kinase (ALK), a receptor tyrosine kinase, was first described as the fusion product causing a subtype of non-Hodgkin's lymphoma [9].

Biological context of Acvrl1

• An Acvrl1(+/-) mouse with profound liver involvement also displayed a secondary cardiac phenotype, similar to that observed in human patients [10].
• In contrast to Alk1 mutants, endoglin mutants do not show profound vessel dilation or downregulation of arterial ephrinB2 [11].
• Isolation of a regulatory region of activin receptor-like kinase 1 gene sufficient for arterial endothelium-specific expression [12].
• We created a novel null mutant mouse line for Alk1 (Alk1lacZ) by replacing its exons, including the one that encodes the transmembrane domain, with the beta-galactosidase gene [13].
• Alk1 expression is greatly diminished in adult arteries, but is induced in preexisting feeding arteries and newly forming arterial vessels during wound healing and tumor angiogenesis [13].

Anatomical context of Acvrl1

• Our results indicate a pivotal role for endoglin in the balance of ALK1 and ALK5 signalling to regulate endothelial cell proliferation [7].
• Using Alk1lacZ mice, we show that Alk1 is predominantly expressed in developing arterial endothelium [13].
• Contrary to the current view of HHT as venous disease, our findings suggest that the arterioles rather than the venules are the primary vessels affected by the loss of an Alk1 allele, and that blood vessels with reduction in Alk1 expression may harbor defects in responding to demands for vascular remodeling [13].
• An activin receptor-like kinase (ALK) 4/5/7 inhibitor, SB431542, also antagonised both oocyte and GDF9 bioactivity in a dose-dependent manner [14].
• In this study, we have analyzed the temporal and spatial expression pattern of ALK-1 mRNA in mouse embryos from the one-cell zygote until 12.5 dpc using RT-PCR and in situ hybridization [15].

Associations of Acvrl1 with chemical compounds

• We have previously identified a series of type I serine/threonine kinase receptors, termed activin receptor-like kinase (ALK)-1 to -6 [16].
• Expression of ALK-1, a type 1 serine/threonine kinase receptor, coincides with sites of vasculogenesis and angiogenesis in early mouse development [15].
• This genetic abnormality leads to the expression of the NPM-ALK fusion protein, which encodes a constitutively active tyrosine kinase that plays a causative role in lymphomagenesis [4].

Physical interactions of Acvrl1

• BACKGROUND: In endothelial cells (EC), transforming growth factor-beta (TGF-beta) can bind to and transduce signals through ALK1 and ALK5 [17].

Regulatory relationships of Acvrl1

• Endoglin null endothelial cells proliferate faster and are more responsive to transforming growth factor beta1 with higher affinity receptors and an activated Alk1 pathway [18].
• TGF-beta/ALK1-induced Smad1/5 phosphorylation in ECs occurs transiently [17].

Other interactions of Acvrl1

• It was shown that mutations in the Alk1 gene in mice and zebrafish resulted in an embryonic lethal phenotype due to severe dilation of blood vessels [13].
• Smad7 and protein phosphatase 1alpha (PP1alpha) mRNA expression levels were found to be specifically upregulated by TGF-beta/ALK1 [17].
• 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 [19].
• Dephosphorylation of the ALK1, immunoprecipitated from cell lysates, was attenuated by a specific PP1 inhibitor [17].

Analytical, diagnostic and therapeutic context of Acvrl1

• The similarity of affected organs, age-dependent penetrance, histological similarity of the lesions and recapitulation of a secondary phenotype suggest that the Acvrl1(+/-) mice are an appropriate animal model for the identification of additional genetic and environmental factors that cause pathology in HHT type 2 patients [10].
• To define the function of ALK1 during development, we inactivated the ALK1 gene in mice by gene targeting [1].
• On Western blots, a goat polyclonal antibody detected the native ALK-1 protein in bone marrow stromal cells, lung, brain, kidney and spleen [20].

References