CD44v6 promotes proliferation by persisting activation of MAP kinases.
CD44v6 is transiently expressed during T cell activation, and constitutively CD44v4-v7 expressing transgenic T cells show accelerated responses towards nominal antigens. The underlying mechanism is unknown. The mouse thymoma EL4 was transfected with CD44 standard isoform (CD44s) or CD44v6 cDNA (EL4-s, EL4-v6). Only EL4-v6 cells proliferated at an over 10-fold higher rate than untransfected cells, displayed up-regulated expression of CD69, CD25, and IL-2, and were protected from apoptosis by CD44v6 cross-linking. In the absence of any stimulus, ERK1/2 was partly phosphorylated, and phosphorylation was significantly increased by CD44v6 cross-linking. The same accounted for JNK, c-jun, and IkappaBalpha. Moreover, NF-kappaB was partly translocated into the nucleus. Instead, CD44s cross-linking induced ERK1/2, JNK, c-jun, and IkappaBalpha phosphorylation only in the context of TCR engagement. No selectively CD44v6 associated transmembrane proteins were uncovered in EL4 cells. However, CD44v6, as opposed to CD44s, did not colocalise with the TCR/CD3 complex after CD3 cross-linking. Furthermore, a CD44-associated 85-kDa protein became hypophosphorylated only after CD44v6 cross-linking. Threonine hypophosphorylation of this protein coincided with the activation of MAP and SAP kinases, which was prohibited in the presence of a phosphatase inhibitor. Thus, CD44v6, distinct to CD44s, stimulates autonomously growth and IL-2 secretion of a thymoma line and rescues cells from apoptosis.
Marhaba
Rachid
R
Department of Tumor Progression and Tumor Defense, German Cancer Research Center, Heidelberg.
Bourouba
Mehdi
M
Zöller
Margot
M
D000818:Animals; D017209:Apoptosis; D019921:Biotinylation; D015153:Blotting, Western; D017252:CD3 Complex / Q000096:biosynthesis; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003432:Cross-Linking Reagents / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D003720:Densitometry; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006023:Glycoproteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D013945:Thymoma / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
D017252:CD3 Complex; C112697:CD44v6 antigen; D003432:Cross-Linking Reagents; D018076:DNA, Complementary; D006023:Glycoproteins; D018960:Hyaluronan Receptors; D007376:Interleukin-2; D020033:Protein Isoforms; D015375:Receptors, Interleukin-2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3