ALCAM/CD166 adhesive function is regulated by the tetraspanin CD9.
ALCAM/CD166 is a member of the immunoglobulin superfamily of cell adhesion molecules (Ig-CAMs) which mediates intercellular adhesion through either homophilic (ALCAM-ALCAM) or heterophilic (ALCAM-CD6) interactions. ALCAM-mediated adhesion is crucial in different physiological and pathological phenomena, with particular relevance in leukocyte extravasation, stabilization of the immunological synapse, T cell activation and proliferation and tumor growth and metastasis. Although the functional implications of ALCAM in these processes is well established, the mechanisms regulating its adhesive capacity remain obscure. Using confocal microscopy colocalization, and biochemical and functional analyses, we found that ALCAM directly associates with the tetraspanin CD9 on the leukocyte surface in protein complexes that also include the metalloproteinase ADAM17/TACE. The functional relevance of these interactions is evidenced by the CD9-induced upregulation of both homophilic and heterophilic ALCAM interactions, as reflected by increased ALCAM-mediated cell adhesion and T cell migration, activation and proliferation. The enhancement of ALCAM function induced by CD9 is mediated by a dual mechanism involving (1) augmented clustering of ALCAM molecules, and (2) upregulation of ALCAM surface expression due to inhibition of ADAM17 sheddase activity.
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, Campus de Cantoblanco, 28049, Madrid, Spain.
Alvaro
A
Gilsanz
Lorena
L
Sánchez-Martín
María Dolores
MD
Gutiérrez-López
Susana
S
Ovalle
Yesenia
Y
Machado-Pineda
Raquel
R
Reyes
Guido W
GW
Swart
Carl G
CG
Figdor
Esther M
EM
Lafuente
Carlos
C
Cabañas
D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D006224:Cricetinae; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D007962:Leukocytes / Q000378:metabolism; D011485:Protein Binding; D060066:Protein Interaction Maps; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D060245:Tetraspanin 29 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D020410:Activated-Leukocyte Cell Adhesion Molecule; D034741:RNA, Small Interfering; D060245:Tetraspanin 29; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human