Phosphorylation of Thr695 and Thr850 on the myosin phosphatase target subunit: Inhibitory effects and occurrence in A7r5 cells

Murányi, Andrea; Derkach, Dmitry N.; Erdõdi, Ferenc; Kiss, Andrea; M, Ito; Hartshorne, David J.

doi:10.1016/j.febslet.2005.10.055

Cited by 132 publications

(147 citation statements)

References 37 publications

(48 reference statements)

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“…However, the reason for the apparent discrepancy between these two studies (17,19) remains unclear. In fact, the phosphorylation sites T696 and T853 are each flanked by amino acid sequences similar to those flanking the phosphorylation site of MLC20.…”

Section: Inhibition Of the Mlcp Activity By Mypt1 Phosphorylationmentioning

confidence: 89%

“…This effect of T853 phosphorylation could therefore decrease the phosphatase activity of MLCP toward MLC20. Recently, the phosphorylation at T853 has also been reported to contribute to the inhibition of the MLCP activity (19). -calmodulin-dependent myosin light chain kinase; MLCP, myosin light chain phosphatase; MYPT1, myosin phosphatase target subunit 1 of MLCP; M20, 20-kDa non-catalytic subunit of MLCP; PAK, p21-activated protein kinase; PI3K-C2α, α isoform of the class II phosphatidylinositol 3-kinase; PKC, protein kinase C; PKN, protein kinase N; PLC, phospholipase C; PP1c, a catalytic subunit of type 1 protein phosphatase; RhoGEF, GDP-GTP exchange factor of RhoA; RhoK, Rho-kinase, representing two isoforms of ROCKI and ROCK II; ZIPK, zipper-interacting protein kinase.…”

Section: Inhibition Of the Mlcp Activity By Mypt1 Phosphorylationmentioning

confidence: 99%

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Current Topics in the Regulatory Mechanism Underlying the Ca2+ Sensitization of the Contractile Apparatus in Vascular Smooth Muscle

2007

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Abstract. The Ca2+ signal is the primary determinant of the contraction of the vascular smooth muscle. However, the alteration of the Ca 2+ sensitivity of the contractile apparatus also plays an essential role. The regulation of the myosin light chain phosphatase (MLCP) activity is considered to be the most important mechanism underlying the regulation of Ca 2+ sensitivity. The investigations during the last 15 years have identified many proteins that participate in the regulation of the MLCP activity. Recently, the Ca 2+ signal has also been shown to cross-talk with the mechanisms regulating the Ca 2+ sensitivity. Consequently, Rho kinase, protein kinase C, CPI-17, and MYPT1 have all been suggested to play a physiologically important role in the regulation of the MLCP activity. We are now close to elucidating the major rules regulating the MLCP activity and the Ca 2+ sensitivity during vascular contractions. This article will give an overview of the current understanding of the biochemical basis for the regulation of the MLCP activity, while also discussing their functional roles from a physiological point of view. I hope this article will help to develop new pharmacological strategies for the prevention and treatment of the pathological vasoconstriction often seen in vascular diseases.

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Section: Inhibition Of the Mlcp Activity By Mypt1 Phosphorylationmentioning

confidence: 89%

Section: Inhibition Of the Mlcp Activity By Mypt1 Phosphorylationmentioning

confidence: 99%

Current Topics in the Regulatory Mechanism Underlying the Ca2+ Sensitization of the Contractile Apparatus in Vascular Smooth Muscle

2007

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“…Phosphorylated CPI-17 at Thr38 inhibits dephosphorylation of the myosin light chain and maintains contraction of smooth muscle (16,17). In addition to CPI-17, phosphorylation of MYPT1 at Thr696 and Thr853 also maintains contraction by inhibiting myosin light chain phosphatase activity (32,33). In intestinal smooth muscle, all of these phosphorylation events involving CPI-17 and MYPT1 are essential for decreasing the activity of myosin light chain phos- phatase (20).…”

Section: Discussionmentioning

confidence: 99%

IL-17A Induces Hypo-contraction of Intestinal Smooth Muscle via Induction of iNOS in Muscularis Macrophages

et al. 2014

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Abstract.Intestinal inflammation causes disorder in bowel motility. Th17 cytokines are involved in intestinal inflammation. To understand the role of interleukin (IL)-17 in intestinal motility, we examined effects of IL-17A on contractile activities of organ-cultured ileum. Rat ileal smooth muscle strips were organ cultured with IL-17A. Muscle contraction was measured, and cells expressing inducible nitric oxide synthase (iNOS) were identified with immunohistochemistry. Creating Th17-transferred colitis model mice, in vivo effects of IL-17 on contractile activities, and iNOS mRNA expression in colonic smooth muscle were investigated. Treatment with IL-17A for 12 h and 3 days attenuated carbachol-and membrane depolarization-induced contractions in organ-cultured rat ileum. N G -Nitro-l-arginine methyl ester (100 mM), a nitric oxide synthase inhibitor, completely reversed the IL-17A-induced inhibition of contractile force. Ileal tissue cultured in the presence of IL-17A showed increased expression of iNOS mRNA and protein. Immunohistochemical analysis using an iNOS antibody revealed that iNOS protein was expressed on ED2-positive muscularis macrophages. The level of iNOS mRNA was also increased in inflamed colonic smooth muscle of Th17-transferred colitis model mice. In intestinal inflammation, IL-17A induces an intestinal motility disorder through iNOS expression in muscularis macrophages.

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“…We examined the effects of GF-109203x, PD-98059, and SB-203580 on the phosphorylation level of MYPT1 at Thr-697. This is the major site of negative regulation of MLCP activity, although phosphorylation at other sites may also have inhibitory effects (38,54). Ileal smooth muscle tissue was flash frozen 45 min after application of microcystin in the absence and presence of protein kinase inhibitors.…”

Section: Effects Of Y-27632 On Microcystin-induced Contraction Of Ilementioning

confidence: 99%

Characterization of protein kinase pathways responsible for Ca²⁺sensitization in rat ileal longitudinal smooth muscle

Ihara¹,

Moffat²,

Ostrander³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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2ϩsensitization in rat ileal longitudinal smooth muscle. Am J Physiol Gastrointest Liver Physiol 293: G699-G710, 2007. First published July 26, 2007; doi:10.1152/ajpgi.00214.2007.-We investigated the protein kinases responsible for myosin regulatory light chain (LC20) phosphorylation and regulation of myosin light chain phosphatase (MLCP) activity during microcystin (phosphatase inhibitor)-induced contraction at low Ca 2ϩ concentrations of rat ileal smooth muscle stretched in the longitudinal axis. Application of 1 M microcystin induced LC20 diphosphorylation and contraction of ␤-escin-permeabilized rat ileal smooth muscle at pCa 9. The PKC inhibitor GF109203x, the MEK inhibitor PD-98059, and the p38 MAPK inhibitor SB-203580 significantly reduced this contraction. These inhibitory effects were abolished when the microcystin concentration was increased to 10 M, indicating that application of these kinase inhibitors generated an increase in MLCP activity. GF-109203x and PD-98059, but not SB-203580, significantly decreased the phosphorylation level of the myosin-targeting subunit of MLCP, MYPT1, at Thr-697 (rat sequence) during microcystin-induced contraction at pCa 9. On the other hand, SB-203580, but not GF-109203x or PD-98059, significantly reduced the phosphorylation level of the PKC-potentiated phosphatase inhibitor of 17 kDa (CPI-17). A zipper-interacting protein kinase (ZIPK) inhibitor (SM1 peptide) and a Rho-associated kinase inhibitor (Y-27632) had little effect on microcystin-induced contraction at pCa 9. In conclusion, PKC, ERK1/2, and p38 MAPK pathways facilitate microcystin-induced contraction at low Ca 2ϩ concentrations by contributing to the inhibition of MLCP activity either through phosphorylation of MYPT1 or CPI-17 [probably mediated by integrin-linked kinase (ILK)]. ILK and not ZIPK is likely to be the protein kinase responsible for LC20 diphosphorylation during microcystin-induced contraction of rat ileal smooth muscle at pCa 9, similar to its recently described role in vascular smooth muscle. The negative regulation of MLCP by PKC and MAPKs during microcystin-induced contraction at pCa 9, which is not observed in vascular smooth muscle, may be unique to phasic smooth muscle. ileum; protein kinase C; myosin phosphatase; mitogen-activated protein kinase; protein kinase C-potentiated phosphatase inhibitor protein of 17 kDa; myosin-targeting subunit of myosin light chain phosphatase SMOOTH MUSCLE CONTRACTION is a dynamic and highly regulated process. The contractile state of smooth muscle is mainly regulated by phosphorylation of the 20-kDa myosin regulatory light chain (LC 20 ] i )} is the primary determinant of smooth muscle contraction. Force can be further increased through signaling pathways that modulate MLCK and/or MLCP activities. The Ca 2ϩ sensitivity of contraction can be affected by any change in the ratio of MLCK:MLCP activity. A decrease in MLCP activity will shift the balance in favor of MLCK, resulting in a greater degree of LC 20 phosphorylation and contraction. The phenomenon of ...

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Phosphorylation of Thr695 and Thr850 on the myosin phosphatase target subunit: Inhibitory effects and occurrence in A7r5 cells

Cited by 132 publications

References 37 publications

Current Topics in the Regulatory Mechanism Underlying the Ca2+ Sensitization of the Contractile Apparatus in Vascular Smooth Muscle

Current Topics in the Regulatory Mechanism Underlying the Ca2+ Sensitization of the Contractile Apparatus in Vascular Smooth Muscle

IL-17A Induces Hypo-contraction of Intestinal Smooth Muscle via Induction of iNOS in Muscularis Macrophages

Characterization of protein kinase pathways responsible for Ca²⁺sensitization in rat ileal longitudinal smooth muscle

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Phosphorylation of Thr695 and Thr850 on the myosin phosphatase target subunit: Inhibitory effects and occurrence in A7r5 cells

Cited by 132 publications

References 37 publications

Current Topics in the Regulatory Mechanism Underlying the Ca2+ Sensitization of the Contractile Apparatus in Vascular Smooth Muscle

Current Topics in the Regulatory Mechanism Underlying the Ca2+ Sensitization of the Contractile Apparatus in Vascular Smooth Muscle

IL-17A Induces Hypo-contraction of Intestinal Smooth Muscle via Induction of iNOS in Muscularis Macrophages

Characterization of protein kinase pathways responsible for Ca2+sensitization in rat ileal longitudinal smooth muscle

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Characterization of protein kinase pathways responsible for Ca²⁺sensitization in rat ileal longitudinal smooth muscle