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: Y497 and Y713, But Not the STAT6-Docking Tyrosines, Signal Protection from Apoptosis1
Department of Immunology, Jerome Holland Laboratories, American Red Cross, Rockville, MD 20855
IL-4 is a cytokine with important antiapoptotic activity. We have
analyzed the role that tyrosine-containing domains within the
cytoplasmic tail of IL-4R
play in IL-4-mediated protection from
apoptosis. 32D cells expressing a wt huIL-4R or one truncated at aa
557 were protected by huIL-4 from apoptosis while cells expressing a
receptor truncated at aa 657 were not, suggesting that the
carboxyl-terminal domain signals protection from apoptosis. However,
changing Y713 within this region to phenylalanine had no effect. To
analyze the contribution of tyrosine-containing domains independently,
we transplanted regions of the huIL-4R to a truncated form of the
huIL-2Rß that could not signal protection from apoptosis.
Transplantation of the huIL-4R domains containing Y497 or Y713
partially prevented cell death and together signaled protection from
apoptosis in response to IL-2 as well as the wt IL-2Rß. Mutation of
Y497 and Y713 to phenylalanine inhibited protection. In contrast,
transplantation of the domain containing the potential STAT6-docking
tyrosines alone had no effect, yet it inhibited the protection mediated
by the other domains. Although IL-4R signals Shc and SH2-containing
inositol phosphatase (SHIP) phosphorylation, we could not establish an
association between their activation and protection from apoptosis.
Taken together, this study suggests that the domains of the huIL-4R
containing Y497 and Y713 positively regulate protection from apoptosis
while the domain containing the STAT6 docking sites suppresses this
protection, and that additional signaling molecules other than insulin
receptor substrate-1 (IRS1), Shc, or SHIP may be involved in
antiapoptotic signaling.
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