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Blood, 15 March 2001, Vol. 97, No. 6, pp. 1662-1670
HEMATOPOIESIS
Distinct domains of the human granulocyte-macrophage
colony-stimulating factor receptor  subunit mediate activation of
Jak/Stat signaling and differentiation
Michael B. Lilly,
Marina Zemskova,
Arthur E. Frankel,
Jonathan Salo, and
Andrew S. Kraft
From the Departments of Medicine and Surgery and the
Center for Molecular Biology and Gene Therapy, Loma Linda University,
Loma Linda, CA; the Department of Medicine and the Comprehensive Cancer
Center, Wake Forest University, Winston-Salem, NC; and the Department
of Medicine, University of Colorado Health Science Center, Denver, CO.
The  subunit of the human granulocyte-macrophage
colony-stimulating factor (GM-CSF) receptor has several isoforms that
result from alternative splicing events. Two forms, -1 and -2,
have intracytoplasmic sequences that are identical within a
membrane-proximal domain but differ completely distally. Variant and
mutated GM-CSF receptor subunits, along with the  subunit
(c protein) were expressed in M1 murine leukemia cells.
and the ability of the receptors to signal for differentiation events
and to activate Jak/Stat signaling pathways was examined. All cell
lines expressing both and c proteins exhibited
high-affinity binding of radiolabeled human GM-CSF. Receptor subunits with intact membrane-proximal intracellular domains could
induce expression of the macrophage antigen F4/80 and down-regulate the
expression of CD11b. Addition of recombinant human GM-CSF to cells
expressing -1 subunits induced the expression of CD86 and tyrosine
phosphorylation of Jak-2 and its putative substrates SHPTP-2, Stat-5,
and the GM-CSF receptor c subunit. Cells containing subunits that lacked a distal domain (term-3) or had the alternatively
spliced -2 distal domain showed markedly decreased ability to
support tyrosine phosphorylation of Jak-2 and its substrates or to
up-regulate CD86. Ligand binding induced stable association of the
-1 subunit and c protein. In contrast, the -2
subunit did not stably associate with the c subunit.
These data identify potential molecular mechanisms for differential
signaling of the -1 and -2 proteins. The association of unique
signaling events with the 2 active GM-CSF subunit isoforms offers a
model for variable response phenotypes to the same ligand.
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