Interaction of SAP-1, a transmembrane-type protein-tyrosine phosphatase, with the tyrosine kinase Lck. Roles in regulation of T cell function.
SAP-1 is a transmembrane-type protein-tyrosine phosphatase that is expressed in most tissues but whose physiological functions remain unknown. The cytoplasmic region of SAP-1 has now been shown to bind directly the tyrosine kinase Lck. Overexpression of wild-type SAP-1, but not that of a catalytically inactive mutant of SAP-1, inhibited both the basal and the T cell antigen receptor (TCR)-stimulated activity of Lck in human Jurkat T cell lines. Lck served as a direct substrate for dephosphorylation by SAP-1 in vitro. Overexpression of wild-type SAP-1 in Jurkat cells also: (i) inhibited both the activation of mitogen-activated protein kinase and the increase in cell surface expression of CD69 induced by TCR stimulation; (ii) reduced the extent of the TCR-induced increase in the tyrosine phosphorylation of ZAP-70 or that of LAT; (iii) reduced both the basal level of tyrosine phosphorylation of p62dok, as well as the increase in the phosphorylation of this protein induced by CD2 stimulation; and (iv) inhibited cell migration. These results thus suggest that the direct interaction of SAP-1 with Lck results in inhibition of the kinase activity of the latter and a consequent negative regulation of T cell function.
Ito
Tomokazu
T
Biosignal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8512, Japan.
Okazawa
Hideki
H
Maruyama
Koji
K
Tomizawa
Kyoko
K
Motegi
Sei-ichiro
S
Ohnishi
Hiroshi
H
Kuwano
Hiroyuki
H
Kosugi
Atsushi
A
Matozaki
Takashi
T
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002462:Cell Membrane / Q000201:enzymology; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D017931:DNA Primers; D006801:Humans; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011817:Rabbits; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology / Q000502:physiology*; D014162:Transfection
D017931:DNA Primers; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); C431695:PTPRH protein, human; D017027:Protein Tyrosine Phosphatases; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3