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J. Biol. Chem., Vol. 276, Issue 24, 21387-21396, June 15, 2001
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From the Lefty polypeptides, novel members of the
transforming growth factor-
Lefty Proteins Exhibit Unique Processing and Activate the
MAPK Pathway*
§,
,,,
Department of Pathology and the ** Gene
Therapy and Viral Vector Laboratory, North Shore-Long Island
Jewish Health System and Biomedical Research Center, Manhasset,
New York 11030 and the ¶ Laboratory for Molecular Oncology, Center
for Human Genetics, University of Leuven and the Flanders
Interuniversity Institute for Biotechnology, Herestraat 49, B-3000 Leuven, Belgium
(TGF-) superfamily, are involved in
the formation of embryonic lateral patterning. Members of the TGF-
superfamily require processing for their activation, suggesting
cleavage to be an essential step for lefty activation. Transfection of
different cell lines with lefty resulted in expression of a
42-kDa protein, which was proteolytically processed to release two
polypeptides of 34 and 28 kDa. Since members of the proprotein
convertase (PC) family cleave different TGF- factors and are
involved in the establishment of embryonic laterality, we studied their
role in lefty processing. Cotransfection analysis showed that PC5A
processed the lefty precursor to the 34-kDa form in vivo,
whereas furin, PACE4, PC5B, and PC7 had a limited activity. None of
these PCs showed activity in the processing of the lefty polypeptide to the 28-kDa lefty form. The mutation of the consensus sequences for PC
cleavage in the lefty protein allowed the lefty cleavage sites to be
identified. Mutations of the sequence RGKR to
GGKG (amino acids 74-77) and of RHGR to GHGR
(amino acids 132-135) prevented the proteolytic processing of the
lefty precursor to the 34- and 28-kDa forms, respectively. To identify
the biologically active form of lefty, we studied the effect of lefty
treatment on pluripotent P19 cells. Lefty did not induce Smad2 or Smad5 phosphorylation, Smad2/Smad4 heterodimerization, or nuclear
translocation of Smad2 or Smad4, but activated the MAPK pathway in a
time- and dose-dependent fashion. Further analysis showed
the 28-kDa (but not the 34-kDa) polypeptide to induce MAPK activity.
Surprisingly, the 42-kDa lefty protein was also capable of
inducing MAPK activity, indicating that the lefty precursor is
biologically active. The data support a molecular model of processing
as a mechanism for regulation of lefty signaling.
*
This work was supported in part by Grant CA46866
from the National Institutes of Health and by a grant from Lexon Inc.
(to S. T.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of a fellowship from the Fonds voor Wetenschappelijk
Onderzoek Vlaanderen.
To whom correspondence and reprint requests should be
addressed: Dept. of Pathology, Biomedical Research Center, 350 Community Dr., Manhasset, NY 11030. Tel.: 516-484-0813; Fax:
516-484-2831; E-mail: tabibzadeh@bioscience.org.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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