Phosphorylation of CPI-17, an Inhibitor of Myosin Phosphatase, by Protein Kinase N

Hamaguchi, Tetsuya; M, Ito; Feng, Jianhua; Seko, Tetsuya; Koyama, Mamoru; Machida, Hirofumi; Takase, Koujiro; Amano, Mutsuki; Kaibuchi, Kozo; Hartshorne, David J.; Nakano, Takeshi

doi:10.1006/bbrc.2000.3225

Cited by 83 publications

(65 citation statements)

References 36 publications

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“…In addition, Kitazawa et al (24) have recently reported that CPI-17 phosphorylation is partly blocked by a specific ROCKs inhibitor, Y-27632. It has also been reported that RhoA-activated PKN can activate CPI-17 in vitro (26). These results suggest the possibility that the RhoA/ ROCKs/CPI-17 and/or RhoA/PKN/CPI-17 pathway may also be involved in carbachol-induced contractions in rat ileum.…”

Section: Discussionsupporting

confidence: 63%

Chronic Treatment with Interleukin-1β Attenuates Contractions by Decreasing the Activities of CPI-17 and MYPT-1 in Intestinal Smooth Muscle

Ohama

Hori

Sato

et al. 2003

Journal of Biological Chemistry

113

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Interleukin-1␤ (IL-1␤) is a proinflammatory cytokine that plays a central role in inflammatory bowel disease (IBD). In order to elucidate the mechanism of motility disorders frequently observed in IBD, we investigated the long term effects of IL-1␤ on rat ileal smooth muscle contractility by using an organ culture system. When ileal smooth muscle strips were cultured with IL-1␤ (10 ng/ml), contractions elicited by high K ؉ and carbachol were inhibited in a time-dependent manner. IL-1␤ more strongly inhibited the carbachol-induced contractions than high K ؉ with decreasing myosin light chain phosphorylation. In the ␣-toxin-permeabilized ileal muscle, carbachol with GTP or guanosine 5 -3-O-(thio)triphosphate increased the Ca 2؉ sensitivity of contractile elements, and this G protein-coupled Ca 2؉ sensitization was significantly reduced in the IL-1␤-treated ileum. Among the functional proteins involved in the smooth muscle Ca 2؉ sensitization, CPI-17 expression was significantly reduced after the culture with IL-1␤, whereas the expressions of RhoA, ROCK-I, ROCK-II, MYPT-1, myosin light chain kinase, and myosin phosphatase (PP1) were unchanged. The phosphorylation level of CPI-17 by carbachol was low in accordance with the decrease in CPI-17 expression due to IL-1␤ treatment. In contrast, constitutively phosphorylated MYPT-1 was also decreased in the IL-1␤-treated muscles. These results suggest that long term treatment with IL-1␤ decreases either CPI-17 expression or MYPT-1 phosphorylation, which may result in an increase in myosin phosphatase activity to reduce force generation. Based on these findings, we consider IL-1␤ to be an important mediator of gastrointestinal motility disorders in IBD, and CPI-17 and MYPT-1 are key molecules in the decreased smooth muscle contractility due to IL-1␤.

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Section: Discussionsupporting

confidence: 63%

Chronic Treatment with Interleukin-1β Attenuates Contractions by Decreasing the Activities of CPI-17 and MYPT-1 in Intestinal Smooth Muscle

Ohama

Hori

Sato

et al. 2003

Journal of Biological Chemistry

113

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“…We previously found in rat ileal smooth muscle that carbachol-induced contraction is mainly associated with phosphorylation of CPI-17 at Thr38 rather than MYPT1 phosphorylation at Thr696 [20]. Phosphorylation of CPI-17 due to receptor stimulation is reportedly mediated by PKC, as well as by ROCKs and PKN via RhoA activation [7,10,15,16,20]. In the present study, we demonstrated that carbachol-induced increases in CPI-17 phosphorylation were significantly reduced in organ-cultured ileal tissue treated with 17-estradiol, but no changes in total CPI-17 protein expression were noted.…”

Section: Carbachol-induced Contraction Decreased With Upregulation Ofmentioning

confidence: 99%

17.BETA.-Estradiol Induces Gastrointestinal Motility Disorder by Decreasing CPI-17 Phosphorylation Via Changes in Rho-Family G-Protein Rnd Expression in Small Intestine

2009

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ABSTRACT. In the present study, we investigated the long-term effects of 17-estradiol on the motility of small intestine in in vitro organ culture and in vivo treatment studies. When rat ileal circular smooth muscle tissues were cultured with 17-estradiol (0.1 and 1 M) for 5 days, carbachol-induced contraction was inhibited. In ileal tissue isolated from ovariectomized rat treated with 17-estradiol (200 g/ kg/day s.c. for 3 days), carbachol-induced contraction was also impaired. Both in vitro and in vivo, 17-estradiol treatment upregulated heat shock protein 27 (HSP27) expression, indicating the activation of estrogen receptor in the intestinal smooth muscle. 17-estradiol did not change protein expression levels of RhoA and RhoA-associated coiled coil-forming serine/threonine kinases (ROCKs); however, it upregulated Rnd2 and Rnd3, Rho-family G-proteins that counteract the functions of RhoA, both in vitro and in vivo. In organ culture, treatment of ileal tissue with 17-estradiol greatly suppressed the carbachol-induced increase in phosphorylation at Thr38 in CPI-17 without altering total CPI-17 protein expression. These results suggest that 17-estradiol upregulates Rnd expression to inhibit the RhoAmediated Ca 2+ sensitization of contractile mechanisms, which are mediated by CPI-17 phosphorylation in ileal smooth muscle. This mechanism may contribute to the intestinal motility disorder occurring in gender-dependent bowel diseases.

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“…4C demonstrates that CPI-17 physically interacts with PP1␣, evaluated by co-immunoprecipitation, which leads to inhibition of phosphatase activity (27). In addition to being potentiated by PKC, CPI-17 has also been shown to be activated by ROCK and PKN (28,29). Therefore, we determined if exogenous expression of CPI-17 in COS7 cells could inhibit PP1␣ repression of MEF2 activity.…”

Section: Depolarization Enhances Mef2-dependent Gene Expression Throumentioning

confidence: 99%

A Novel RhoA/ROCK-CPI-17-MEF2C Signaling Pathway Regulates Vascular Smooth Muscle Cell Gene Expression

Pagiatakis

Gordon

Ehyai

et al. 2012

Journal of Biological Chemistry

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Background: MEF2C is essential for vascular smooth muscle development, yet the signaling pathways that regulate its function in this cell type remain largely unknown. Results: We identify a novel regulator of MEF2C in vascular smooth muscle, called CPI-17. Conclusion: Our data identify a genetic pathway involving CPI-17, MEF2C, and myocardin. Significance: These findings have important ramifications during vascular development and for stem cell programming.

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Phosphorylation of CPI-17, an Inhibitor of Myosin Phosphatase, by Protein Kinase N

Cited by 83 publications

References 36 publications

Chronic Treatment with Interleukin-1β Attenuates Contractions by Decreasing the Activities of CPI-17 and MYPT-1 in Intestinal Smooth Muscle

Chronic Treatment with Interleukin-1β Attenuates Contractions by Decreasing the Activities of CPI-17 and MYPT-1 in Intestinal Smooth Muscle

17.BETA.-Estradiol Induces Gastrointestinal Motility Disorder by Decreasing CPI-17 Phosphorylation Via Changes in Rho-Family G-Protein Rnd Expression in Small Intestine

A Novel RhoA/ROCK-CPI-17-MEF2C Signaling Pathway Regulates Vascular Smooth Muscle Cell Gene Expression

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