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Point mutations in the conserved box 1 region inactivate the human
granulocyte colony-stimulating factor receptor for growth signal
transduction and tyrosine phosphorylation of p75c-rel
BR Avalos, MG Hunter, JM Parker, SK Ceselski, BJ Druker, SJ Corey and VB Mehta
Arthur G. James Cancer Hospital and Research Institute, Ohio State
University, Columbus 43210, USA.
The human granulocyte colony-stimulating factor receptor (hG-CSFR) belongs
to the cytokine receptor superfamily. As with other members of this family,
the cytoplasmic domain of hG-CSFR lacks intrinsic tyrosine kinase activity.
To identify critical regions mediating growth signal transduction by
hG-CSFR, deletions or site-directed amino acid substitutions were
introduced into the cytoplasmic domain of hG-CSFR, and the mutant cDNAs
were transfected into the murine interleukin-3 (IL- 3)-dependent Ba/F3 and
FDCP cell lines. Truncation of the carboxy- terminal end of the receptor to
the membrane-proximal 53 amino acids of the cytoplasmic domain, which
retained the conserved Box 1 and Box 2 sequence motifs, decreased the
ability of hG-CSFR to transduce G-CSF- mediated growth signals without an
associated loss in receptor binding affinity. Substitution of proline by
alanine at amino acid positions 639 and 641 within Box 1 completely
abolished the G-CSF-mediated growth signal. Rapid induction of tyrosine
phosphorylation of several cellular proteins, including a 75-kD protein
(p75) identified as c-rel, was an early event associated with transduction
of proliferative signals by hG- CSFR in Ba/F3 transfectants. Mutant
receptors containing Pro-to-Ala substitutions that inactivated the receptor
for mitogenic activity also inactivated the receptor for tyrosine-specific
phosphorylation of p75. These results show that the conserved Box 1
sequence motif (amino acids 634 to 641) is critical for mitogenesis and
activation of cellular tyrosine kinases by hG-CSFR.
Volume 85,
Issue 11,
pp. 3117-3126,
06/01/1995
Copyright © 1995 by The American Society of Hematology
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