Cell & Developmental Biology
Open Access

Kinase Action and Function of TPL2 Gene

Kwong Claus^{* *}Correspondence: Kwong Claus, Department of Health Sciences, Hamburg University, Hamburg, Germany, Email:

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Description

Tumor progression locus 2 (TPL2) gene belongs to the MAP3K family of protein kinases. The rat homologue of Cancer Osaka Thyroid (COT) was named TPL2. The two translation initiation sites (M1   and M30)   of   TPL2 equalize the molar concentrations of the 58 kDa (p58) and 52 kDa (p52) proteins. TPL2 is a cytoplasmic protein of 467 amino acids (AA) composed of three parts: amino-terminal (N- terminus), kinase domain (138AA-388AA), Carboxy-terminal (C-terminal), and C-dye-terminal cleavage determinants. Degron, 435aa-457aa is very important for the protein stability of TPL2. However, removal of the C-terminal domain appears to activate the transforming potential of TPL2 through two mechanisms. First, it   has been   suggested   that   truncation of the C-terminus increases the specific kinase activity of TPL2, and that the C-terminus may regulate the catalytic activity of TPL2 by refolding into the kinase domain. Second, the C-terminal truncation removes the degron sequence (amino acids 435-457) that facilitates proteolytic degradation of TPL-2 by the proteasome. A C-terminally truncated sequence 'degron' (435-457) increases kinase-specific activity, suggesting that this region may inhibit TPL2 kinase activity.

TPL2 has important innate immunity in regulating signaling in TNF-α, TLR, and G protein-coupled receptor signaling pathways. Previous studies have shown that TPL2 mediates the production of IL-12 from T cells, which is essential for production of IFN-γ. Stimulation of Tpl2⁻/⁻ CD4⁺ T cells in vitro shows an impaired induction of IFN-γ production and a low rate of differentiation towards a Th1 phenotype. MyD88 is essential for Leishmania eradication. Previous studies have reported that MyD88-deficient mice are more susceptible to Leishmania infection than control mice. These studies also show that lipophosphoglycan, a key parasite molecule, activates innate immune signaling pathways through TLR2. Moreover, in response to infection with the Th1- inducing parasite Toxoplasma gondii, TPL2-deficient mice confer a higher pathogen load associated with reduced systemic IFN-γ production, thereby positively regulating both Th1 responses. It has been defined to promote TPL2 as a factor in both in vitro and in vivo. Thus, reduced levels of two factors, T-bet and Stat4, in TPL2-deficient T cells are essential for their differentiation from Th1 cells. Furthermore, TPL2 knockout mice exhibited decreased IFN-γ production, resulting in increased susceptibility to Toxoplasma gondii infection. Strikingly, TPL2^-/^- mice have an impaired immune response to intracellular Toxoplasma gondii. This is thought to result from T cell autonomic neuropathy rather than alterations in the innate immune response. Such responses are associated with host pathologies that defend against the pathogen Toxoplasma gondii, where IFN induction is impaired and pathogen load is increased. Cot/TPL2⁻/⁻ mice display Th1-skewed antigen- specific immune responses after in vivo immunization and primary infection with leishmaniasis, suggesting that Cot/TPL2 is a key negative regulator of Th1-type adaptive immunity. It also suggests that Dinucleotide CG (CpG-DNA)-rich bacterial DNA activated ERK in a Cot/TPL2-independent manner. Peritoneal macrophages and bone marrow-derived DCs from Cot/TPL2⁻/⁻ mice produced significantly more IL-12 in response to CpG DNA than those from WT mice. Immunization of Cot/TPL2-/- mice with ova and Freund's Complete Adjuvant (CFA or FCA) effectively expanded antigen-specific T cells and increased IFN-γ production. Since Ig class, switching is regulated by cytokines from T cells. These findings are consistent with high IL-12 production and suggest that systemic responses to exogenous antigens in Cot/TPL2⁻/⁻ mice are Th1 type.

If TPL2 contributes to the CD28 co-stimulatory signal, TPL2 deficiency could impair CD28 co-stimulation and thus affect IFN-γ production. Parasite burden was increased in TPL2⁻/⁻mice that survived parasite infection compared with wild-type mice. These findings suggest that TPL2 is essential for IFN-γ production in CD4⁺ T cells.