Cell-matrix interaction via CD44 is independently regulated by different metalloproteinases activated in response to extracellular Ca(2+) influx and PKC activation.
CD44 is an adhesion molecule that interacts with hyaluronic acid (HA) and undergoes sequential proteolytic cleavages in its ectodomain and intramembranous domain. The ectodomain cleavage is triggered by extracellular Ca(2+) influx or the activation of protein kinase C. Here we show that CD44-mediated cell-matrix adhesion is terminated by two independent ADAM family metalloproteinases, ADAM10 and ADAM17, differentially regulated in response to those stimuli. Ca(2+) influx activates ADAM10 by regulating the association between calmodulin and ADAM10, leading to CD44 ectodomain cleavage. Depletion of ADAM10 strongly inhibits the Ca(2+) influx-induced cell detachment from matrix. On the other hand, phorbol ester stimulation activates ADAM17 through the activation of PKC and small GTPase Rac, inducing proteolysis of CD44. Furthermore, depletion of ADAM10 or ADAM17 markedly suppressed CD44-dependent cancer cell migration on HA, but not on fibronectin. The spatio-temporal regulation of two independent signaling pathways for CD44 cleavage plays a crucial role in cell-matrix interaction and cell migration.
Nagano
Osamu
O
Dept. of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Murakami
Daizo
D
Hartmann
Dieter
D
De Strooper
Bart
B
Saftig
Paul
P
Iwatsubo
Takeshi
T
Nakajima
Motowo
M
Shinohara
Masanori
M
Saya
Hideyuki
H
D051722:ADAM Proteins; D000072199:ADAM12 Protein; D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D021982:Cell-Matrix Junctions / Q000502:physiology*; D004622:Embryo, Mammalian; D004789:Enzyme Activation; D005347:Fibroblasts / Q000502:physiology / Q000648:ultrastructure; D018960:Hyaluronan Receptors / Q000502:physiology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D045726:Metalloproteases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism*
D018960:Hyaluronan Receptors; D008565:Membrane Proteins; D009124:Muscle Proteins; D011493:Protein Kinase C; D045726:Metalloproteases; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C096115:Adam12 protein, mouse; D002118:Calcium