Abstract
Protein kinases (PKs) play critical roles in signal transduction and activation of lymphocytes. The identification of PK genes provides a tool for understanding mechanisms of immunotoxic xenobiotics. As part of a larger study investigating persistent organic pollutants in the harbor seal and their possible immunomodulatory actions, we sequenced harbor seal cDNA fragments encoding PKs. The procedure, using degenerate primers based on conserved motifs of human protein tyrosine kinases (PTKs), successfully amplified nine phocid PK gene fragments with high homology to human and rodent orthologs. We identified eight PTKs and one dual (serine/threonine and tyrosine) kinase. Among these were several PKs important in early signaling events through the B- and T-cell receptors (FYN, LYN, ITK and SYK) and a MAP kinase involved in downstream signal transduction. V-FGR, RET and DDR2 were also expressed. Sequential activation of protein kinases ultimately induces gene transcription leading to the proliferation and differentiation of lymphocytes critical to adaptive immunity. PKs are potential targets of bioactive xenobiotics, including persistent organic pollutants of the marine environment; characterization of these molecules in the harbor seal provides a foundation for further research illuminating mechanisms of action of contaminants speculated to contribute to large-scale die-offs of marine mammals via immunosuppression.
Highlights
Protein kinases (PKs) play critical roles in cellular functions including signal transduction, cell cycle regulation, cell division and cell differentiation (Hunter et al, 1985; Edelman et al, 1987)
Certain polycyclic aromatic hydrocarbons (PAHs) have been shown to activate protein tyrosine kinases (PTKs) in human cell lines—FYN and LCK in T-cells and LYN and SYK in B cells (Archuleta et al, 1993; Mounho and Burchiel, 1998). These authors reported that mobilization of intracellular calcium was coupled to increased tyrosine phosphorylation, and suggested that PAH-induced PTK activation and increased cellular Ca2þ may alter antigen receptor signaling in human B cells
Clones positive for PK transcripts were generated from all three seals, and multiple clones were identified for most kinases
Summary
Protein kinases (PKs) play critical roles in cellular functions including signal transduction, cell cycle regulation, cell division and cell differentiation (Hunter et al, 1985; Edelman et al, 1987). Signal transduction through the B- and T-cell receptors (BCR and TCR, respectively) and cytokine receptors on the surface of lymphocytes occurs largely via tyrosine phosphorylation of intracellular substrates by protein tyrosine kinases (PTKs). These authors reported that mobilization of intracellular calcium was coupled to increased tyrosine phosphorylation, and suggested that PAH-induced PTK activation and increased cellular Ca2þ may alter antigen receptor signaling in human B cells.
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