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Vol. 57, Issue 5, 840-846, May 2000
Laboratory of Cellular Carcinogenesis and Tumor Promotion, National
Cancer Institute, Bethesda, Maryland (P.S.L., M.B., P.M.B.); Department
of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
(J.C.S.); and the Cancer Research Institute, Arizona State University,
Tempe, Arizona (G.R.P.)
RasGRP is a recently described guanine nucleotide exchange factor (GEF)
that possesses a single C1 domain homologous to that of protein kinase
C (PKC). The phorbol ester [3H]phorbol 12,13-dibutyrate
([3H]PDBu) bound to this C1 domain (C1-RasGRP) with a
dissociation constant of 0.58 ± 0.08 nM, similar to that observed
previously for PKC. Likewise, the potent PKC activator bryostatin 1, a
compound currently in clinical trials, showed high affinity binding for C1-RasGRP. Structure activity analysis using several phorbol ester analogs showed both similarities and differences in ligand selectivity compared with PKC; the differences were comparable in magnitude to
those between different PKC isoforms. Similarly, the potency of the PKC
inhibitor calphostin C to inhibit [3H]PDBu binding to
C1-RasGRP was similar to that observed for PKC. In contrast to the
relative similarities in ligand recognition, the lipid cofactor
requirements differed between RasGRP and PKC. The C1 domain plus the
EF-hand motif of RasGRP (C1EF-RasGRP) was markedly less dependent on
acidic phospholipids than was PKC
. The differences in lipid
requirements were reflected in differential ligand selectivity under
conditions of limiting lipid. Despite the presence of twin EF-hand like
motifs, calcium did not affect the binding of [3H]PDBu to
C1EF-RasGRP. We conclude that RasGRP is a high affinity receptor for
phorbol esters and diacylglycerol. RasGRP thus provides a direct link
between diacylglycerol generation or phorbol ester/bryostatin treatment
and Ras activation.
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