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PMID: 17045821 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex.

Immunity ·Vol. 25 ·No. 4 ·2006-10-00 ·Pages 595-606

Shi X, Leng L, Wang T, Wang W, Du X, Li J, McDonald C, Chen Z, Murphy JW, Lolis E, Noble P, Knudson W, Bucala R

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.

MeSH Terms
Animals Antigens, Differentiation, B-Lymphocyte/genetics,metabolism Apoptosis COS Cells CSK Tyrosine-Protein Kinase Chlorocebus aethiops Histocompatibility Antigens Class II/genetics,metabolism Humans Hyaluronan Receptors/genetics,metabolism Macrophage Migration-Inhibitory Factors/metabolism Mice Mice, Knockout Mitogen-Activated Protein Kinase 1/metabolism Mitogen-Activated Protein Kinase 3/antagonists & inhibitors,metabolism Phosphorylation Protein-Tyrosine Kinases/metabolism Serine/metabolism Signal Transduction Tumor Suppressor Protein p53 src-Family Kinases
Chemicals
Antigens, Differentiation, B-Lymphocyte Histocompatibility Antigens Class II Hyaluronan Receptors Macrophage Migration-Inhibitory Factors Tumor Suppressor Protein p53 invariant chain Serine Protein-Tyrosine Kinases CSK Tyrosine-Protein Kinase src-Family Kinases CSK protein, human Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Shi Xuerong
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Leng Lin
Wang Tian
Wang Wenkui
Du Xin
Li Ji
McDonald Courtney
Chen Zun
Murphy James W
Lolis Elias
Noble Paul
Knudson Warren
Bucala Richard
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Article Info
Journal
Immunity
Abbr.
Immunity
ISSN
1074-7613
DOI
10.1016/j.immuni.2006.08.020
Published
2006-10-00
Pages
595-606
Language
English
Region
United States
NLM ID
9432918
PMCID
PMC3707630
Subset
IM
Grants
NIAMS NIH HHS · R01 AR043384 · United States
NHLBI NIH HHS · R01 HL060539 · United States
NIAMS NIH HHS · R01 AR050498 · United States
NIAID NIH HHS · R01 AI065029 · United States
NHLBI NIH HHS · HL060539 · United States
NIAID NIH HHS · R56 AI042310 · United States
NIAMS NIH HHS · R01 AR049610 · United States
NIAID NIH HHS · AI42310 · United States
NIAMS NIH HHS · AR050498 · United States
NIAMS NIH HHS · AR049610 · United States
NIAMS NIH HHS · R01 AR043384-13 · United States
NIAMS NIH HHS · AR43384 · United States
NIAID NIH HHS · R01 AI042310 · United States
NIAID NIH HHS · R01 AI065029-02 · United States
External Links
PubMed source DOI: 10.1016/j.immuni.2006.08.020 PMC Full Text View journal details
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