Regulation of myosin light-chain phosphorylation and its roles in cardiovascular physiology and pathophysiology

M, Ito; Okamoto, Ryuji; Ito, Hiromasa; Zhe, Ye; Dohi, Kaoru

doi:10.1038/s41440-021-00733-y

Cited by 25 publications

(13 citation statements)

References 183 publications

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“…The regulatory myosin light chain (MLC/Myl9) is the main regulatory protein controlling actin contraction and phosphorylated MLC (p-MLC) is found on the cytoskeletal contractile units. MLC is activated by phosphorylation that in turn is dually regulated by a phosphatase (MLCP) and a kinase (MLCK) 20 . Deregulated MLC phosphorylation has been associated with aneurysms and cardiovascular pathologies 20,21 .…”

Section: Resultsmentioning

confidence: 99%

Coordination between cytoskeletal organization, cell contraction and extracellular matrix development, is depended on LOX for aneurysm prevention

Aviram,

Zaffryar-Eilot,

Kaganovsky

et al. 2024

Preprint

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Distinct, seemingly independent, cellular pathways affecting intracellular machineries or extracellular matrix (ECM) deposition and organization, have been implicated in aneurysm formation. One of the key genes associated with the pathology in both humans and mice is Lysyl oxidase (LOX), a secreted ECM-modifying enzyme, highly expressed in medial vascular smooth muscle cells. To dissect the mechanisms leading to aneurysm development, we conditionally deletedLoxin smooth muscle cells. We find that cytoskeletal organization is lost followingLoxdeletion. Cell culture assays and in vivo analyses demonstrate a cell-autonomous role for LOX affecting myosin light chain phosphorylation and cytoskeletal assembly resulting in irregular smooth muscle contraction. These results not only highlight new intracellular roles for LOX, but notably they link between multiple processes leading to aneurysm formation suggesting LOX coordinates ECM development, cytoskeletal organization and cell contraction required for media development and function.

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Section: Resultsmentioning

confidence: 99%

Coordination between cytoskeletal organization, cell contraction and extracellular matrix development, is depended on LOX for aneurysm prevention

Aviram,

Zaffryar-Eilot,

Kaganovsky

et al. 2024

Preprint

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“…Strikingly, among both the PPP family phosphatases (Tables 1 and S2) and the non-PPP family phosphatases (Table 2) whose phosphorylation changes in response to LH, many have known functions in regulating the cytoskeleton and cell motility. Among the PPP family phosphatase regulatory proteins showing large LH-induced changes in phosphorylation intensity (Table 1), PPP1R12A (MYPT1) and PPP1R14A (CPI-17) are regulators of myosin light chain phosphorylation (52), which controls non-muscle myosin assembly and contractility (53). Other PPP family regulatory subunits that show large LH- induced changes in phosphorylation intensity (Table S2) include HDAC6, which regulates tubulin (54), and FARP1, PHACTR4, and PHACTR2, which regulate actin (55, 56).…”

Section: Resultsmentioning

confidence: 99%

Phosphatases modified by LH signaling in ovarian follicles: testing their role in regulating the NPR2 guanylyl cyclase

Egbert

Silbern

Uliasz

et al. 2023

Preprint

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In response to luteinizing hormone, multiple proteins in rat and mouse granulosa cells are rapidly dephosphorylated, but the responsible phosphatases remain to be identified. Because the phosphorylation state of phosphatases can regulate their interaction with substrates, we searched for phosphatases that might function in LH signaling by using quantitative phosphomass spectrometry. We identified all proteins in rat ovarian follicles whose phosphorylation state changed detectably in response to a 30-minute exposure to LH, and within this list, identified protein phosphatases or phosphatase regulatory subunits that showed changes in phosphorylation. Phosphatases in the PPP family were of particular interest because of their requirement for dephosphorylating the natriuretic peptide receptor 2 (NPR2) guanylyl cyclase, which triggers oocyte meiotic resumption. Among the PPP family regulatory subunits, PPP1R12A and PPP2R5D showed the largest increases in phosphorylation, with 4-10 fold increases in signal intensity on several sites. Although follicles from mice in which these phosphorylations were prevented by serine-to-alanine mutations in either Ppp1r12a or Ppp2r5d showed normal LH-induced NPR2 dephosphorylation, these regulatory subunits and others could act redundantly to dephosphorylate NPR2. Our identification of phosphatases and other proteins whose phosphorylation state is rapidly modified by LH provides clues about multiple signaling pathways in ovarian follicles.

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“…Strikingly, among both the PPP family phosphatases (Tables 1 and S2) and the non-PPP family phosphatases (52, 53) (Table 2) whose phosphorylation changes in response to LH, many have known functions in regulating the cytoskeleton and cell motility. Among the PPP family phosphatase regulatory proteins showing large LH-induced changes in phosphorylation intensity (Table 1), PPP1R12A (MYPT1) and PPP1R14A (CPI-17) are regulators of myosin light chain phosphorylation (54), which controls non-muscle myosin assembly and contractility (55). Other PPP family regulatory subunits that show large LH-induced changes in phosphorylation intensity () include HDAC6, which regulates tubulin (56), and FARP1, PHACTR4, and PHACTR2, which regulate actin (57, 58).…”

Section: Resultsmentioning

confidence: 99%

Phosphatases modified by LH signaling in ovarian follicles: testing their role in regulating the NPR2 guanylyl cyclase

Egbert,

Silbern,

Uliasz

et al. 2023

Biology of Reproduction

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In response to luteinizing hormone, multiple proteins in rat and mouse granulosa cells are rapidly dephosphorylated, but the responsible phosphatases remain to be identified. Because the phosphorylation state of phosphatases can regulate their interaction with substrates, we searched for phosphatases that might function in LH signaling by using quantitative mass spectrometry. We identified all proteins in rat ovarian follicles whose phosphorylation state changed detectably in response to a 30-minute exposure to LH, and within this list, identified protein phosphatases or phosphatase regulatory subunits that showed changes in phosphorylation. Phosphatases in the PPP family were of particular interest because of their requirement for dephosphorylating the natriuretic peptide receptor 2 (NPR2) guanylyl cyclase in the granulosa cells, which triggers oocyte meiotic resumption. Among the PPP family regulatory subunits, PPP1R12A and PPP2R5D showed the largest increases in phosphorylation, with 4–10 fold increases in signal intensity on several sites. Although follicles from mice in which these phosphorylations were prevented by serine-to-alanine mutations in either Ppp1r12a or Ppp2r5d showed normal LH-induced NPR2 dephosphorylation, these regulatory subunits and others could act redundantly to dephosphorylate NPR2. Our identification of phosphatases and other proteins whose phosphorylation state is rapidly modified by LH provides clues about multiple signaling pathways in ovarian follicles.

show abstract

Regulation of myosin light-chain phosphorylation and its roles in cardiovascular physiology and pathophysiology

Cited by 25 publications

References 183 publications

Coordination between cytoskeletal organization, cell contraction and extracellular matrix development, is depended on LOX for aneurysm prevention

Coordination between cytoskeletal organization, cell contraction and extracellular matrix development, is depended on LOX for aneurysm prevention

Phosphatases modified by LH signaling in ovarian follicles: testing their role in regulating the NPR2 guanylyl cyclase

Phosphatases modified by LH signaling in ovarian follicles: testing their role in regulating the NPR2 guanylyl cyclase

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