Mitogen-activated protein kinase pathway activation by the CD6 lymphocyte surface receptor.
CD6 is a cell surface receptor primarily expressed on immature thymocytes and mature T and B1a lymphocytes. Through its binding to activated leukocyte cell adhesion molecule (ALCAM/CD166), CD6 is considered to play an important role in lymphocyte development and activation. Accordingly, CD6 associates with the TCR/CD3 complex and colocalizes with it at the center of the mature immunological synapse on T lymphocytes. Moreover, the CD6-ALCAM interaction has been shown to be critical for proper immunological synapse maturation and T cell proliferative responses. However, the precise biological effects of CD6 ligation and its signaling pathway are still not well understood. The present study shows that CD6 ligation with three different specific mAbs (161.8, SPV-L14.2, and MAE1-C10) induces time- and dose-dependent activation of ERK1/2 on normal and leukemic human T cells. This effect was also observed upon CD6 ligation with a chimerical ALCAM protein (ALCAM-Fc). The C-terminal cytoplasmic region of CD6, as well as Src tyrosine kinases, was critical for CD6-induced ERK1/2 activation. Synergistic effects were observed upon coligation of the TCR/CD3 complex with CD6. The ligation of CD6 induced the transcriptional activation of reporter genes under the control of the c-Fos serum responsive element and AP-1. Accordingly, CD6-mediated activation of p38 and JNK was also observed. These findings indicate that the CD6-ALCAM interaction results in activation of the three MAPK cascades, likely influencing the dynamic balance that determines whether resting or activated lymphocytes survive or undergo apoptosis.
Ibáñez
Anna
A
Servei d'Immunologia, Hospital Clínic i Provincial de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de Medicina, Universitat de Barcelona, Villaroel 170, 08036 Barcelona, Spain.
Sarrias
Maria-Rosa
MR
Farnós
Montserrat
M
Gimferrer
Idoia
I
Serra-Pagès
Carles
C
Vives
Jordi
J
Lozano
Francisco
F
D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000378:metabolism / Q000502:physiology; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D003593:Cytoplasm / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D004790:Enzyme Induction / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000276:immunology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis / Q000378:metabolism; D010446:Peptide Fragments / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D015854:Up-Regulation / Q000276:immunology; D019061:src-Family Kinases / Q000502:physiology
D020410:Activated-Leukocyte Cell Adhesion Molecule; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; C062279:CD6 antigen; D008024:Ligands; D010446:Peptide Fragments; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3