Autoimmunity

T-cell receptor signaling activates the kinase MAP4K3 (also named GLK) by inducing its direct interaction with the upstream adaptor protein SLP-76. Activated GLK directly phosphorylates and activates PKC-θ, which is required for NF-κB activation in T cells. Moreover, GLK-defi cient mice show impaired Th 17 diff erentiation and are resistant to IL-17A mediated experimental autoimmune encephalomyelitis (EAE). Consistently, autoimmune SLE and rheumatoid arthritis (RA) patients show signifi cantly increased GLK levels in T cells; the percentage of GLK-overexpressing T cells is correlated with autoimmune disease severity. Recently, we generated and characterized T-cell specifi c GLK transgenic (Lck-GLK Tg) mice and found that these transgenic mice spontaneously develop autoimmune diseases with an induction of systemic inflammation and an increase of autoantibodies (ANA, anti-dsDNA, rheumatoid factor). We found that GLK signaling specifi cally induced IL-17A transcription in the T cells of GLK transgenic mice. Moreover, the induction of serum IL-17A and autoantibodies in Lck-GLK Tg mice was abolished by treatment of a GLK inhibitor. Th e disease severity and serum IL-17A levels in EAE or collagen-induced arthritis mouse models were also attenuated by the GLK inhibitor treatment. In addition, GLK protein levels were also overexpressed in tumor tissues of lung cancer or hepatoma patients. Th e GLK overexpression was correlated with increased recurrence risks and poor recurrence-free survival rates of lung cancer and hepatoma. Collectively, MAP4K3/GLK is a novel diagnostic/prognostic biomarker and therapeutic target for cancer and IL-17A-mediated autoimmune diseases.