Abstract
Raf Kinase Inhibitor Protein1 (RKIP) is a tumor suppressor that is present in several adult tissues. It functions as an inhibitor of both Raf/Mek/Erk and NFĸB signaling when unphosphorylated, but following phosphorylation the ability to inhibit Raf/Mek/Erk signaling is lost and RKIP becomes an activator of G-protein coupled receptor signaling. In neonates and adults, RKIP is known to be expressed in muscle; however, its physiological function is currently unknown. In this study, we show by in situ hybridization and immunofluorescence that RKIP is also expressed in developing chick embryonic muscle, and mouse C2C12 myoblasts. Furthermore, we demonstrate that, in these systems, it functions as an inhibitor of myogenesis: increased levels of RKIP suppress myotube differentiation whereas decreasing RKIP promotes differentiation. Additionally, we show that the ability of RKIP to inhibit myogenesis is dependent upon its phosphorylation state as only the nonphosphorylated form of RKIP suppresses myogenesis. This study, therefore, clearly demonstrates that RKIP has conserved functions as a myogenic inhibitor in both mammalian and avian muscle. Developmental Dynamics 245:902-912, 2016. © 2016 Wiley Periodicals, Inc.
Highlights
Raf Kinase Inhibitor Protein1 (RKIP) is a member of the phosphatidylethanolamine binding (PEBP) protein family
We show that RKIP is expressed in developing embryonic muscles of the chick and both myoblasts and myotubes in C2C12 cultures
We demonstrate that in both chick and mouse RKIP regulates the rate at which myoblasts differentiate into myotubes, and that in mouse this function is dependent on its phosphorylation state
Summary
Raf Kinase Inhibitor Protein (RKIP) is a member of the phosphatidylethanolamine binding (PEBP) protein family. The first pathway shown to be regulated by RKIP was the MAP kinase pathway (Yeung et al, 1999) In this context RKIP binds to Raf, or its target MEK, and inhibits their interaction blocking the ability of Raf to phosphorylate and activate MEK and inhibiting downstream ERK signalling. This discovery was closely followed by the finding that RKIP binds and inhibits kinases that regulate other signalling pathways, including NFĸB inducing kinase, Tak (Yeung et al, 2001) and GRK2 (Lorenz et al, 2003). We demonstrate that in both chick and mouse RKIP regulates the rate at which myoblasts differentiate into myotubes, and that in mouse this function is dependent on its phosphorylation state
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