Human retroviral gag- and gag-pol-like proteins interact with the transforming growth factor-beta receptor activin receptor-like kinase 1.
Mutations in activin receptor-like kinase 1 (ALK1), a transforming growth factor (TGF)-beta type I receptor, lead to the vascular disorder hereditary hemorrhagic telangiectasia caused by abnormal vascular remodeling. The underlying molecular cause of this disease is not well understood. Identifying binding partners for ALK1 will help to understand its cellular function. Using the two-hybrid system, we identified an ALK1-binding protein encoded by an ancient retroviral/retrotransposon element integrated as a single copy gene known as PEG10 on human chromosome 7q21. PEG10 contains two overlapping reading frames from which two proteins, PEG10-RF1 and PEG10-RF1/2, are translated by a typical retroviral -1 ribosomal frameshift mechanism. Reverse transcription-PCR and Northern blot analysis showed a broad range of PEG10 expression in different tissues and cell types, i.e. human placenta, brain, kidney, endothelial cells, lymphoblasts, and HepG2 and HEK293 cells. However, endogenous PEG10-RF1 and PEG10-RF1/2 proteins were only detected in HepG2 and HEK293 cells. PEG10-RF1, which is the major PEG10 protein product, represents a gag-like protein, and PEG10-RF1/2 represents a gag-pol-like protein. PEG10-RF1 also interacts with different members of TGF-beta superfamily type I and II receptors. PEG10-RF1 binding to ALK1 is mediated by a 200-amino acid domain with no recognized motif. PEG10-RF1 inhibits ALK1 as well as ALK5 signaling. Co-expression of ALK1 and PEG10-RF1 in different cell types induced morphological changes reminiscent of neuronal cells or sprouting cells. This is the first report of a human retroviral-like protein interacting with members of the TGF-beta receptor family.
Lux
Andreas
A
University Hospital Mannheim and Institute of Molecular Biology and Cell Culture Technology, University of Applied Sciences Mannheim, 68163 Mannheim, Germany. a.lux@fh-mannheim.de
Beil
Christian
C
Majety
Meher
M
Barron
Suzanne
S
Gallione
Carol J
CJ
Kuhn
Hella-Monika
HM
Berg
Jonathan N
JN
Kioschis
Petra
P
Marchuk
Douglas A
DA
Hafner
Mathias
M
D030201:Activin Receptors, Type I / Q000378:metabolism*; D030301:Activin Receptors, Type II; D020816:Amino Acid Motifs; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D016466:CHO Cells; D019556:COS Cells; D002460:Cell Line; D003001:Cloning, Molecular; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism; D004251:DNA Transposable Elements; D015685:Fusion Proteins, gag-pol / Q000378:metabolism*; D015723:Gene Library; D015683:Gene Products, gag / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D016366:Open Reading Frames; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014018:Tissue Distribution; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D020298:U937 Cells
D004251:DNA Transposable Elements; D015685:Fusion Proteins, gag-pol; D015683:Gene Products, gag; D016212:Transforming Growth Factor beta; D008156:Luciferases; C425364:ACVRL1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II