Abstract
Monocyte to macrophage differentiation is characterized by the activation of various signal transduction pathways, which may be modulated by protein phosphorylation; however, the impact of protein kinases and phosphatases is not well understood yet. It has been demonstrated that actomyosin rearrangement during macrophage differentiation is dependent on Rho-associated protein kinase (ROCK). Myosin phosphatase (MP) target subunit-1 (MYPT1) is one of the major cellular substrates of ROCK, and MP is often a counter enzyme of ROCK; therefore, MP may also control macrophage differentiation. Changes in MP activity and the effects of MP activation were studied on PMA or l,25(OH)2D3-induced differentiation of monocytic THP-1 cells. During macrophage differentiation, phosphorylation of MYPT1 at Thr696 and Thr853 increased significantly, resulting in inhibition of MP. The ROCK inhibitor H1152 and the MP activator epigallocatechin-3-gallate (EGCG) attenuated MYPT1 phosphorylation and concomitantly decreased the extent of phosphorylation of 20 kDa myosin light chain. H1152 and EGCG pretreatment also suppressed the expression of CD11b and weakened the PMA-induced adherence of the cells. Our results indicate that MP activation/inhibition contributes to the efficacy of monocyte to macrophage differentiation, and this enzyme may be a target for pharmacological interventions in the control of disease states that are affected by excessive macrophage differentiation.
Highlights
Protein phosphatase-1 (PP1) and -2A (PP2A) enzymes play important roles in cellular signaling pathways via dephosphorylation of a large number of phosphoproteins [22,23,24]; little is known about their function during monocytic differentiation
Protein kinases and phosphatases might play a vital role in the guidance of macrophage differentiation as important regulators of cellular signaling
Ser/Thr-specific phosphatases have a well-documented role in the regulation of various cellular processes; there are only a few reports demonstrating the involvement of phosphatases in the control of signaling pathways that regulate macrophage differentiation
Summary
Monocytes and macrophages are important mediators of innate immune responses and inflammatory processes. Understanding the differentiation process at molecular level and the description of regulatory mechanisms behind may aid in the identification of new therapeutic targets. Protein phosphorylation is one fundamental regulatory mechanism for many cellular processes and signal transduction pathways. The level of protein phosphorylation is determined by the opposing action of protein kinases and phosphatases. Members of these two enzyme families have been implicated in the control of a plethora of cell functions; their role in the regulation of signaling pathways during monocyte to macrophage differentiation has not been revealed in every aspect
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