CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex.
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.
Shi
Xuerong
X
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Leng
Lin
L
Wang
Tian
T
Wang
Wenkui
W
Du
Xin
X
Li
Ji
J
McDonald
Courtney
C
Chen
Zun
Z
Murphy
James W
JW
Lolis
Elias
E
Noble
Paul
P
Knudson
Warren
W
Bucala
Richard
R
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D019556:COS Cells; D000081247:CSK Tyrosine-Protein Kinase; D002522:Chlorocebus aethiops; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53; D019061:src-Family Kinases
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D018960:Hyaluronan Receptors; D008263:Macrophage Migration-Inhibitory Factors; D016159:Tumor Suppressor Protein p53; C045084:invariant chain; D012694:Serine; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3