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(Received for publication, December 13, 1996, and in revised form, February 20, 1997)
From the Division of Medical Oncology, Department of Medicine,
University of Colorado Health Sciences Center,
Denver, Colorado 80262
Granulocyte-macrophage colony-stimulating factor
(GM-CSF), interleukin (IL)-3, and IL-5 stimulate DNA synthesis and
proliferation and inhibit apoptosis in hematopoietic cells. Multiple
signal pathways are activated by binding of these ligands to their
receptors, which share a common 
subunit. Janus protein kinase 2 (Jak2) binds to the membrane proximal domain of the chain and is
phosphorylated on receptor ligation. To explore the role of Jak2 in the
regulation of specific signal transduction pathways, we constructed
fusion proteins with a CD16 external domain, a CD7 transmembrane
region, and a Jak2 cytoplasmic domain. This cytoplasmic domain
consisted either of wild type Jak2 (CD16/Jak2-W) or Jak2 mutations with deletions of (a) the amino terminus (CD16/Jak2-N),
(b) kinase-like domain (CD16/Jak2-B), (c)
kinase domain (CD16/Jak2-C), or (d) amino-terminal and
kinase-like domains, leaving the kinase domain (CD16/Jak-K) intact. In
contrast to the CD16/Jak2-W fusion protein, which requires
cross-linking for activation, CD16/Jak2-N, CD16/Jak2-B, and CD16/Jak2-K
were constitutively phosphorylated, and they stimulated Shc
phosphorylation and increased binding of STAT to DNA in Ba/F3 cells.
Cell lines derived from IL-3-dependent Ba/F3 cells stably transfected with CD16/Jak2-W, CD16/Jak2-N, or CD16/Jak2-B mammalian expression vectors died at a rate similar to that of the parental cells
on IL-3 deprivation. In contrast, CD16/Jak2-K cell lines exhibited
increased expression of bcl-2 and pim-1
mRNA and maintained their viability when compared with control cell
lines. Thus, activation of tyrosine phosphorylation by creating a
CD16/Jak2-K fusion is sufficient to activate pathways that prevent cell
death.
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