HTLV-I Tax induces and associates with Crk-associated substrate lymphocyte type (Cas-L).
Crk-associated substrate lymphocyte type (Cas-L) is a docking protein that is heavily tyrosine phosphorylated by the engagement of beta1 integrins in T cells. In the present study, we attempted to evaluate the role of Cas-L in the pathophysiology of adult T-cell leukemia (ATL). Examination of peripheral blood mononuclear cells from ATL patients as well as ATL-derived T cell lines showed an elevation of Cas-L in these cells. We showed that tyrosine phosphorylation as well as expression of Cas-L was markedly elevated through the induction of human T-lymphotropic virus type I (HTLV-I) Tax in JPX-9 cells, with these cells showing marked motile behavior on the ligands for integrins. We next performed yeast two-hybrid screening of cDNA library from an HTLV-I-transformed T cell line, which resulted in the identification of Tax as a putative binding partner for Cas-L. Co-precipitation experiments revealed that the serine-rich region of Cas-L might serve as the binding site with the highest affinity for Tax. Co-localization study showed that Tax and Cas-L partly merged in the cytoplasm. Finally, we showed that exogenous Cas-L inhibited Tax-mediated transactivation of nuclear factor kappaB (NF-kappaB), while Tax-independent activation of NF-kappaB remained intact, hence indicating that Cas-L might specifically regulate Tax-NF-kappaB pathway.
Iwata
Satoshi
S
Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Souta-Kuribara
Akiko
A
Yamakawa
Akio
A
Sasaki
Takahiro
T
Shimizu
Takatsune
T
Hosono
Osamu
O
Kawasaki
Hiroshi
H
Tanaka
Hirotoshi
H
Dang
Nam H
NH
Watanabe
Toshiki
T
Arima
Naomichi
N
Morimoto
Chikao
C
D048868:Adaptor Proteins, Signal Transducing; D019256:Cadmium Chloride / Q000494:pharmacology; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D003600:Cytosol / Q000737:chemistry; D016356:Gene Products, tax / Q000032:analysis / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D015458:Leukemia, T-Cell / Q000821:virology*; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D010750:Phosphoproteins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D015533:Transcriptional Activation / Q000502:physiology; D020798:Two-Hybrid System Techniques; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D016356:Gene Products, tax; C099942:NEDD9 protein, human; D016328:NF-kappa B; D010750:Phosphoproteins; D019256:Cadmium Chloride