Vascular Smooth Muscle Cell Motility Is Mediated by a Physical and Functional Interaction of Ca2+/Calmodulin-dependent Protein Kinase IIδ2 and Fyn

Ginnan, Roman; Zou, Xiaojing; Pfleiderer, Paul; Mercure, Melissa Z.; Barroso, Margarida; Singer, Harold A.

doi:10.1074/jbc.m113.477257

Cited by 15 publications

(18 citation statements)

References 48 publications

(21 reference statements)

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“…Adherence led to CaMKII-dependent tyrosine phosphorylation of paxillin and ERK activation ( Lu et al, 2005 ). The CaMKII delta 2 variant has also been shown to regulate vascular smooth muscle cell motility in culture through a Src-family tyrosine kinase, Fyn ( Ginnan et al, 2013 ). Because focal adhesions are known to serve as ERK scaffolds in contractile smooth muscle, this is an appealing possible link.…”

Section: Vascular Smooth Muscle Signal Transductionmentioning

confidence: 99%

Mechanisms of Vascular Smooth Muscle Contraction and the Basis for Pharmacologic Treatment of Smooth Muscle Disorders

et al. 2016

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The smooth muscle cell directly drives the contraction of the vascular wall and hence regulates the size of the blood vessel lumen. We review here the current understanding of the molecular mechanisms by which agonists, therapeutics, and diseases regulate contractility of the vascular smooth muscle cell and we place this within the context of whole body function. We also discuss the implications for personalized medicine and highlight specific potential target molecules that may provide opportunities for the future development of new therapeutics to regulate vascular function.

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Section: Vascular Smooth Muscle Signal Transductionmentioning

confidence: 99%

Mechanisms of Vascular Smooth Muscle Contraction and the Basis for Pharmacologic Treatment of Smooth Muscle Disorders

et al. 2016

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“…A direct functional interaction between CaMK-IIδ 2 and the downstream Src-family kinase Fyn has been demonstrated. This is followed by the activation of Fyn mediated by the previous dephosphorylation of its regulatory Tyr527 residue, and hence the coordinated regulation of VSMC migration by both kinases [129].…”

Section: Cam-dependent Phosphorylationmentioning

confidence: 99%

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

Villalobo

Berchtold

2020

IJMS

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Calmodulin (CaM) is the principal Ca2+ sensor protein in all eukaryotic cells, that upon binding to target proteins transduces signals encoded by global or subcellular-specific changes of Ca2+ concentration within the cell. The Ca2+/CaM complex as well as Ca2+-free CaM modulate the activity of a vast number of enzymes, channels, signaling, adaptor and structural proteins, and hence the functionality of implicated signaling pathways, which control multiple cellular functions. A basic and important cellular function controlled by CaM in various ways is cell motility. Here we discuss the role of CaM-dependent systems involved in cell migration, tumor cell invasiveness, and metastasis development. Emphasis is given to phosphorylation/dephosphorylation events catalyzed by myosin light-chain kinase, CaM-dependent kinase-II, as well as other CaM-dependent kinases, and the CaM-dependent phosphatase calcineurin. In addition, the role of the CaM-regulated small GTPases Rac1 and Cdc42 (cell division cycle protein 42) as well as CaM-binding adaptor/scaffold proteins such as Grb7 (growth factor receptor bound protein 7), IQGAP (IQ motif containing GTPase activating protein) and AKAP12 (A kinase anchoring protein 12) will be reviewed. CaM-regulated mechanisms in cancer cells responsible for their greater migratory capacity compared to non-malignant cells, invasion of adjacent normal tissues and their systemic dissemination will be discussed, including closely linked processes such as the epithelial–mesenchymal transition and the activation of metalloproteases. This review covers as well the role of CaM in establishing metastatic foci in distant organs. Finally, the use of CaM antagonists and other blocking techniques to downregulate CaM-dependent systems aimed at preventing cancer cell invasiveness and metastasis development will be outlined.

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“…Well‐documented examples include an 11 aa sequence, that results in nuclear targeting of holoenzymes (9) and variable domains in some β subunits that link the kinase to the actin cytoskeleton (10). Variable domains in γ (4), and δ subunits (11) have been implicated in binding interactions that could link Ca 2+ signals to intracellular signaling pathways involving nonreceptor tyrosine kinases and ERK1/2 activation. These and yet‐to‐be‐discovered structural variations of CaMKII isoforms could have important functional consequences related to CaMKII‐dependent regulation of VSM cell function.…”

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confidence: 99%

Ca²⁺/calmodulin‐dependent protein kinase II‐γ (CaMKIIγ) negatively regulates vascular smooth muscle cell proliferation and vascular remodeling

et al. 2015

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Vascular smooth muscle (VSM) expresses calcium/calmodulin-dependent protein kinase II (CaMKII)-d and -g isoforms. CaMKIId promotes VSM proliferation and vascular remodeling. We tested CaMKIIg function in vascular remodeling after injury. CaMKIIg protein decreased 90% 14 d after balloon injury in rat carotid artery. Intraluminal transduction of adenovirus encoding CaMKIIg C rescued expression to 35% of uninjured controls, inhibited neointima formation (>70%), inhibited VSM proliferation (>60%), and increased expression of the cell-cycle inhibitor p21 (>2-fold). Comparable doses of CaMKIId 2 adenovirus had no effect. Similar dynamics in CaMKIIg mRNA and protein expression were observed in ligated mouse carotid arteries, correlating closely with expression of VSM differentiation markers. Targeted deletion of CaMKIIg in smooth muscle resulted in a 20-fold increase in neointimal area, with a 3-fold increase in the cell proliferation index, no change in apoptosis, and a 60% decrease in p21 expression. In cultured VSM, CaMKIIg overexpression induced p53 mRNA (1.7 fold) and protein (1.8-fold) expression; induced the p53 target gene p21 (3-fold); decreased VSM cell proliferation (>50%); and had no effect on expression of apoptosis markers. We conclude that regulated CaMKII isoform composition is an important determinant of the injury-induced vasculoproliferative response and that CaMKIIg and -d isoforms have nonequivalent, opposing functions.

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Vascular Smooth Muscle Cell Motility Is Mediated by a Physical and Functional Interaction of Ca2+/Calmodulin-dependent Protein Kinase IIδ2 and Fyn

Cited by 15 publications

References 48 publications

Mechanisms of Vascular Smooth Muscle Contraction and the Basis for Pharmacologic Treatment of Smooth Muscle Disorders

Mechanisms of Vascular Smooth Muscle Contraction and the Basis for Pharmacologic Treatment of Smooth Muscle Disorders

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

Ca²⁺/calmodulin‐dependent protein kinase II‐γ (CaMKIIγ) negatively regulates vascular smooth muscle cell proliferation and vascular remodeling

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Vascular Smooth Muscle Cell Motility Is Mediated by a Physical and Functional Interaction of Ca2+/Calmodulin-dependent Protein Kinase IIδ2 and Fyn

Cited by 15 publications

References 48 publications

Mechanisms of Vascular Smooth Muscle Contraction and the Basis for Pharmacologic Treatment of Smooth Muscle Disorders

Mechanisms of Vascular Smooth Muscle Contraction and the Basis for Pharmacologic Treatment of Smooth Muscle Disorders

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

Ca2+/calmodulin‐dependent protein kinase II‐γ (CaMKIIγ) negatively regulates vascular smooth muscle cell proliferation and vascular remodeling

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Ca²⁺/calmodulin‐dependent protein kinase II‐γ (CaMKIIγ) negatively regulates vascular smooth muscle cell proliferation and vascular remodeling