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T. Yamashita, C. Cook, J. Zuo; RP1 Mediates JNK Signaling . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3741.
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Mutations in the RP1 gene are a common cause of autosomal dominant retinitis pigmentosa. We have previously showed that the Jun–N–terminal kinase (JNK) signaling was reduced in Rp1 knockout (Rp1–/–) mice. Because JNK activation by overexpression of Rac1 active form can rescue rhodopsin null mutant and protect photoreceptor cell death in Drosophila retinas, we sought to ascertain whether RP1 itself promotes JNK signaling and is the target of JNK phosphorylation in photoreceptors.
COS7 cells were transfected with FLAG–tagged Rp1 constructs. Western blot analysis confirmed the expression of Rp1 and phosphorylation of JNK molecules, an assay for JNK activation. Bacterially expressed GST–fused Rp1 proteins were purified using glutathione–sepharose 4B and incubated with recombinant JNK1/2 active forms in the presence or absence of [γ–32P] ATP. Phosphorylation was visualized by radioactivity and Rp1 phospho–specific antibodies.
Rp1 is involved in signal transduction and can promote JNK signaling in COS7 cells. Rp1 can be phosphorylated at Thr–84 residue by JNK in vitro.
These results suggested cross talks between RP1 and JNK. Therefore RP1 functions not only as a simple microtubule–associated protein (MAP) but also as signaling molecule. We therefore hypothesized that recruitment of JNK to RP1 is necessary for activation of the JNK signaling in photoreceptors. Because the threonine 84 residue of Rp1 is located within the DCX domain, which is known as a microtubule–binding domain, JNK molecules might modulate RP1's microtubule binding activity by Phosphorylating at Thr–84. Because JNK signaling is important for cell survival, these preliminary results may explain why Rp1 knockout and possibly other photoreceptor degenerative mutant mice show photoreceptor degeneration and provide therapeutic targets for disease intervention.
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