CD44 Is the Signaling Component of the Macrophage Migration Inhibitory Factor-CD74 Receptor Complex

Xuerong Shi, Lin Leng, Tian Wang, Wenkui Wang, Xin Du, Ji Li, Courtney McDonald, Zun Chen, James W. Murphy, Elias Lolis, Paul Noble, Warren Knudson, Richard Bucala

Research output: Contribution to journalArticle

391 Scopus citations

Abstract

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 COS-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.

Original languageEnglish (US)
Pages (from-to)595-606
Number of pages12
JournalImmunity
Volume25
Issue number4
DOIs
StatePublished - Oct 1 2006
Externally publishedYes

Keywords

  • MOLIMMUNO
  • SIGNALING

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Shi, X., Leng, L., Wang, T., Wang, W., Du, X., Li, J., McDonald, C., Chen, Z., Murphy, J. W., Lolis, E., Noble, P., Knudson, W., & Bucala, R. (2006). CD44 Is the Signaling Component of the Macrophage Migration Inhibitory Factor-CD74 Receptor Complex. Immunity, 25(4), 595-606. https://doi.org/10.1016/j.immuni.2006.08.020