Journal
IMMUNITY
Volume 25, Issue 4, Pages 595-606Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2006.08.020
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Funding
- NHLBI NIH HHS [HL060539, R01 HL060539] Funding Source: Medline
- NIAID NIH HHS [AI42310, R01 AI042310, R56 AI042310, R01 AI065029, R01 AI065029-02] Funding Source: Medline
- NIAMS NIH HHS [R01 AR043384, AR050498, R01 AR043384-13, R01 AR049610, AR049610, AR43384, R01 AR050498] Funding Source: Medline
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The macrophage migration inhibitory factor (MIF) receptor (CD74) was cloned recently, but the signaling mechanism is not evident. We hypothesized that signaling requires an additional molecule such as CD44, which activates nonreceptor tyrosine kinases. We utilized the CD74- and CD44-deficient CCS-7/M6 cell to create stable transfectants expressing CD74, CD44, and a truncated CD44 lacking its intracytoplasmic signaling domain. CD74 alone mediated MIF binding; however, MIF-induced ERK1 and ERK2 kinase phosphorylation required the coexpression of full-length CD44. MIF binding was associated with the serine phosphorylation of CD74 and CD44. Investigations that used siRNA or kinase inhibitors indicate that MIF-induced ERK1 and ERK2 activation through CD44 required the Src tyrosine kinase. Studies of CD74, CD44, and CD74-CD44 transformants and corresponding mutant cells showed that CD74 and CD44 were necessary for MIF protection from apoptosis. These data establish CD44 as an integral member of the CD74 receptor complex leading to MIF signal transduction.
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