Altered biological activity associated with C-terminal modifications of IL-7.
Interleukin 7 (IL-7) is a pleiotropic cytokine which plays a role in both T and B cell function as well as in establishment and maintenance of immunological barriers in epithelial tissues. The heterodimeric IL-7 receptor (IL-7R) consists of the p76 IL-7Ralpha subunit and the p64 common gamma (gammac) subunit. Ligand-binding induces signal transduction through tyrosine phosphorylation of the janus (Jak) and src-related kinases as well as by activation of phosphatidinositol-3 kinase (P13-kinase). In an effort to further define the requirements for ligand-receptor interactions and to subsequently develop candidate receptor binding antagonists with selective biological activities, we examined a series of IL-7 mutants in which the carboxy terminal hydrophobic residues were substituted with aliphatic amino acids. In this study we describe abrogation of IL-7 driven proliferation and attenuated phosphotyrosine signaling by IL-7(143) (Trp-Ala) and IL-7(143) (Trp-His) in IL-7R expressing T and B leukemia cells. Decreased phosphorylation of Jak3 kinase by IL-7W143A, IL-7W143P and IL-7W143H suggest that alterations in this region of the carboxyterminal region of IL-7 affects its interaction with the gammac subunit of the IL-7R.
Görgün
Güllü
G
Hematology, Oncology and Experimental Therapeutics, Tufts New England Medical Center, 750 Washington Street, Boston, MA 02111, USA.
van der Spek
Johanna
J
Cosenza
Larry
L
Menevse
Adnan
A
Foss
Francine
F
D015153:Blotting, Western; D002455:Cell Division; D006801:Humans; D015851:Interleukin-7 / Q000737:chemistry / Q000502:physiology*; D011233:Precipitin Tests
D015851:Interleukin-7