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J. Biol. Chem., Vol. 277, Issue 28, 25756-25774, July 12, 2002
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From the A cDNA was isolated from interleukin
3-developed, mouse bone marrow-derived mast cells (MCs) that contained
an insert (designated mRasGRP4) that had not been
identified in any species at the gene, mRNA, or protein level. By
using a homology-based cloning approach, the ~2.6-kb
hRasGRP4 transcript was also isolated from the mononuclear progenitors residing in the peripheral blood of normal individuals. This transcript information was then used to locate the
RasGRP4 gene in the mouse and human genomes, to deduce its
exon/intron organization, and then to identify 10 single nucleotide
polymorphisms in the human gene that result in 5 amino acid
differences. The >15-kb hRasGRP4 gene consists of 18 exons
and resides on a region of chromosome 19q13.1 that had not been
sequenced by the Human Genome Project. Human and mouse MCs and their
progenitors selectively express RasGRP4, and this new intracellular
protein contains all of the domains present in the RasGRP family of
guanine nucleotide exchange factors even though it is <50% identical
to its closest homolog. Recombinant RasGRP4 can activate H-Ras in a
cation-dependent manner. Transfection experiments also
suggest that RasGRP4 is a diacylglycerol/phorbol ester receptor.
Transcript analysis of an asthma patient, a mastocytosis patient, and
the HMC-1 cell line derived from a MC leukemia patient revealed the
presence of substantial amounts of non-functional forms of hRasGRP4 due to an inability to remove intron 5 in the precursor transcript. Because
only abnormal forms of hRasGRP4 were identified in the HMC-1 cell line,
this immature MC progenitor was used to address the function of RasGRP4
in MCs. HMC-1 leukemia cells differentiated and underwent granule
maturation when induced to express a normal form of RasGRP4. Thus,
RasGRP4 plays an important role in the final stages of MC development.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF331457, AY040628, AY048119, AY048120, and AY048121.
RasGRP4, a New Mast Cell-restricted Ras Guanine
Nucleotide-releasing Protein with Calcium- and Diacylglycerol-binding
Motifs
IDENTIFICATION OF DEFECTIVE VARIANTS OF THIS SIGNALING PROTEIN
IN ASTHMA, MASTOCYTOSIS, AND MAST CELL LEUKEMIA PATIENTS AND
DEMONSTRATION OF THE IMPORTANCE OF RasGRP4 IN MAST CELL DEVELOPMENT AND
FUNCTION*
§,§,¶,
,
ali**, and§§
Department of Medicine, Brigham and Women's
Hospital, and Department of Medicine, Harvard Medical School,
Boston, Massachusetts 02115, the Department of Medicine,
University of New South Wales, and Department of Immunology,
Allergy, and Infectious Disease, St. George Hospital,
Kogarah, New South Wales 2217, Australia, and
** Laboratories of Molecular Biophysics, Pels Family Center
for Biochemistry and Structural Biology, Rockefeller University,
New York, New York 10021
*
This work was supported by National Institutes of Health
Grants AI-23483, GM-54762, HL-36110, and HL-63284, and by a grant from
the Mizutani Foundation for Glycoscience.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.
Irma T. Hirschl Trust Career Scientist.
§§
To whom correspondence and reprint requests should be addressed:
Brigham and Women's Hospital, Dept. of Medicine, Smith Bldg., Rm.
616B, 1 Jimmy Fund Way, Boston, MA 02115. Tel.: 617-525-1231; Fax:
617-525-1310; E-mail: rstevens@rics.bwh.harvard.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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