Erythropoietin (EPO) stimulates proliferation of early-stage erythrocyte precursors and is widely used for the treatment of chronic anemia. However, several types of EPO-resistant anemia are characterized by defects in late-stage erythropoiesis, which is EPO independent. Here we investigated regulation of erythropoiesis using a ligand-trapping fusion protein (ACE-536) containing the extracellular domain of human activin receptor type IIB (ActRIIB) modified to reduce activin binding. ACE-536, or its mouse version RAP-536, produced rapid and robust increases in erythrocyte numbers in multiple species under basal conditions and reduced or prevented anemia in murine models. Unlike EPO, RAP-536 promoted maturation of late-stage erythroid precursors in vivo. Cotreatment with ACE-536 and EPO produced a synergistic erythropoietic response. ACE-536 bound growth differentiation factor-11 (GDF11) and potently inhibited GDF11-mediated Smad2/3 signaling. GDF11 inhibited erythroid maturation in mice in vivo and ex vivo. Expression of GDF11 and ActRIIB in erythroid precursors decreased progressively with maturation, suggesting an inhibitory role for GDF11 in late-stage erythroid differentiation. RAP-536 treatment also reduced Smad2/3 activation, anemia, erythroid hyperplasia and ineffective erythropoiesis in a mouse model of myelodysplastic syndromes (MDS). These findings implicate transforming growth factor-β (TGF-β) superfamily signaling in erythroid maturation and identify ACE-536 as a new potential treatment for anemia, including that caused by ineffective erythropoiesis.
Endoglin (CD105), a transmembrane protein of the transforming growth factor  superfamily, plays a crucial role in angiogenesis. Mutations in endoglin result in the vascular defect known as hereditary hemorrhagic telangiectasia (HHT1). The soluble form of endoglin was suggested to contribute to the pathogenesis of preeclampsia. To obtain further insight into its function, we cloned, expressed, purified, and characterized the extracellular domain (ECD) of mouse and human endoglin fused to an immunoglobulin Fc domain. We found that mouse and human endoglin ECD-Fc bound directly, specifically, and with high affinity to bone morphogenetic proteins 9 and 10 (BMP9 and BMP10) in surface plasmon resonance (Biacore) and cell-based assays. We performed a function mapping analysis of the different domains of endoglin by examining their contributions to the selectivity and biological activity of the protein. Endoglin (CD105) is a homodimeric glycosylated cell-surface protein of 180 kDa previously identified as a co-receptor belonging to the TGF superfamily (1). Several lines of evidence support an important role of endoglin in cardiovascular development and vascular remodeling (2). Loss-of-function mutations in endoglin are implicated in the vascular disorder hereditary hemorrhagic telangiectasia type 1 (HHT1), 3 which is a bleeding disorder characterized by arteriovenous malformations in the brain, lungs, and liver and is attributed to haploinsufficiency (3-5). Homozygous endoglin knock-out mice die during early gestation due to the lack of development of normal mature blood vessels (6). Adult endoglin heterozygous mice (7-8) or mice with a conditional mutation in the endoglin gene (9) exhibited similar angiogenic abnormalities and were used as animal models for HHT1. Mutations in the endoglin gene found in numerous HHT1 patients are localized most exclusively in the extracellular domain (4). The specific role of endoglin in the vascular dysplasia observed in HHT patients is not known, but it is likely to be related to the role of TGF family signaling in angiogenesis (2, 10). Interestingly, another form of HHT, known as HHT2, which is also characterized by the presence of telangiectases as well as arteriovenous malformations in brain, lungs and liver, results from the loss of TGF type I receptor ALK1 (11), which suggests an interrelatedness between endoglin and ALK1 and possibly involvement of the same ligand(s) in the mechanism of action of both molecules.A soluble form of endoglin has been observed in the serum of patients with different types of solid malignancies (12) and of pregnant women suffering from preeclampsia, a disease leading to vascular permeability (13), hypertension, and placental abruption (14). This soluble form, which reportedly results from partial shedding of the membrane-bound form of endoglin by the matrix metalloproteinase 14 (MT1-MMP) (15), a phenomenon also observed for the other type III receptor betaglycan (16), has been proposed to act as a scavenger or trap for circulating TGF family liga...
Background: Activin receptor-like kinase 1 (ALK1) is an important regulator of normal blood vessel formation and pathological tumor angiogenesis. Results: Crystal structure of ALK1-BMP9-ACTRIIB signaling complex and kinetic and thermodynamic properties of receptorligand interactions are described. Conclusions: ALK1 achieves high specificity for BMP9/10 through unusual receptor positioning and unique receptor-ligand interface. Significance: Structural and mechanistic insights into ALK1 signaling provide a framework for novel anti-angiogenic therapies.
Cholesterol is an essential structural element of cellular membranes as well as a precursor for the synthesis of steroid hormones, bile acids, and lipoproteins. Mammalian cells obtain cholesterol by internalization of low density lipoproteins (LDL) 1 or by de novo synthesis in the endoplasmic reticulum (ER). Deposition of excess cellular cholesterol in the form of cholesteryl esters is catalyzed by acyl CoA:cholesterol acyltransferase (ACAT), a resident ER enzyme. Rates of cholesterol biosynthesis, LDL internalization, and cholesterol esterification are exquisitely sensitive to cellular levels of free cholesterol. Just as cellular levels of cholesterol are tightly controlled, so is its compartmentation. Cholesterol is not uniformly distributed among cell membranes (1, 2) or within membranes (3,4). The mechanisms that sort cholesterol to particular membranes or domains are not well understood. This review will highlight recent work on cellular cholesterol distribution, membrane cholesterol domains, and the intracellular trafficking of cholesterol. Other recent reviews by Liscum and Dahl (5), Rothblat et al. (3), Glaser (4), Liscum and Faust (6), and Trotter and Voelker (7) may also prove interesting to the reader.
We report the cloning and characterization of a novel membrane-bound, calcium-independent PLA 2 , named cPLA 2 -␥. The sequence encodes a 541-amino acid protein containing a domain with significant homology to the catalytic domain of the 85-kDa cPLA 2 (cPLA 2 -␣). cPLA 2 -␥ does not contain the regulatory calcium-dependent lipid binding (CaLB) domain found in cPLA 2-␣. However, cPLA 2 -␥ does contain two consensus motifs for lipid modification, a prenylation motif (؊CCLA) at the C terminus and a myristoylation site at the N terminus. We present evidence that the isoprenoid precursor [ 3 H]mevalonolactone is incorporated into the prenylation motif of cPLA 2 -␥. Interestingly, cPLA 2 -␥ demonstrates a preference for arachidonic acid at the sn-2 position of phosphatidylcholine as compared with palmitic acid. cPLA 2 -␥ encodes a 3-kilobase message, which is highly expressed in heart and skeletal muscle, suggesting a specific role in these tissues. Identification of cPLA 2 -␥ reveals a newly defined family of phospholipases A 2 with homology to cPLA 2 -␣.
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