The Effector Domain of Myristoylated Alanine-rich C Kinase Substrate Binds Strongly to Phosphatidylinositol 4,5-Bisphosphate

Wang, Jiyao; Arbuzova, Anna; Hangyás-Mihályné, Gyöngyi; McLaughlin, Stuart

doi:10.1074/jbc.m008355200

Cited by 171 publications

(189 citation statements)

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“…The regulatory mechanisms of the PLC ␦ isoform family are not well understood (Cockcroft and Thomas 1992); however, one of the mechanisms that cause a decrease in PLC ␦ 1 could be related to altered levels of PIP 2 . It has been reported that MARCKS inhibits the activity of PLC ␦ 1 by binding with a significant fraction of PIP 2 (Wang et al 2001). Because a change in PIP 2 levels has been reported in platelets of bipolar patients (Soares et al 2000) and because we observed an increase in levels of MARCKS in platelets of bipolar patients, it is possible that alterations in the levels of PIP 2, probably caused by binding of MARCKS, may result in decreased PI-PLC activity and PLC ␦ 1 levels.…”

Section: Discussionmentioning

confidence: 47%

“…In the present study, we found that MARCKS levels are increased in bipolar patients, and hence this increase may cause decreases in hydrolysis of PIP 2 by inhibiting PI-PLC activity, because MARCKS interacts with PIP 2 substrate and inhibits the PLC-catalyzed hydrolysis of PIP 2 and the expression of PLC ␦ 1 (Wang et al 2001).…”

Section: Discussionmentioning

confidence: 49%

“…It has been suggested that a possible mechanism may be the action of PKC on one of its main substrates, MARCKS. That alterations of MARCKS may be involved in bipolar illness is derived from the observation that lithium causes decreased MARCKS expression in immortalized hippocampal cells and rat hippocampus (Watson et al 1994, Watson and Lenox 1996, Wang et al 2001). To our knowledge, MARCKS has not been studied in patients with bipolar or unipolar illness.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have demonstrated that MARCKS and a peptide corresponding to its basic effector domain (151-175) inhibit PI-specific PLC-catalyzed hydrolysis of PIP 2 in vesicles (Glaser et al 1996), and it is also reported that the addition of 10-100 nM MARCKS (151-175) to a subphase containing either PLC ␦ 1 and ␤ 1 inhibits hydrolysis of PIP 2 (Wang et al 2001). In the present study, we found that MARCKS levels are increased in bipolar patients, and hence this increase may cause decreases in hydrolysis of PIP 2 by inhibiting PI-PLC activity, because MARCKS interacts with PIP 2 substrate and inhibits the PLC-catalyzed hydrolysis of PIP 2 and the expression of PLC ␦ 1 (Wang et al 2001).…”

Section: Discussionmentioning

confidence: 99%

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Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients

Pandey

Dwivedi

SridharaRao

et al. 2002

Neuropsychopharmacology

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Phospholipase C (PLC) and protein kinase C (PKC) are important components of the phosphoinositide (PI) signaling system. To examine if the abnormalities observed in the PIdrolysis of the substrate, phosphatidyl inositol 4,5-bisphosphate (PIP 2 ), by the enzyme phospholipase C (PLC), resulting in the formation of two second messengers, inositol 1,4,5-trisphophate (IP 3 ) and diacylglycerol (DAG) (Berridge and Irvine 1989). IP 3 stimulates the release of intracellular calcium from the endoplasmic reticulum, and DAG stimulates the enzyme protein kinase C (PKC) (Nishizuka 1992), which is one of the major intracellular mediators of signals generated by the stimulation of cell surface receptors.Several studies indicate abnormalities of the PI signaling system in patients with unipolar or bipolar disorders. It has been reported that the hydrolysis of PIP 2 by several agonists, such as sodium fluoride (NaF) and GTP ␥ S, is altered in the postmortem brain of depressed Pacheco et al. 1996). PI signal transduction determined by serotonin (5HT)-, thrombin-, and NaF-stimulated IP formation has also been reported to be increased in platelets of depressed patients (Mikuni et al. 1991;Karege et al. 1996). These abnormalities may be related to abnormalities in receptors, such as 5HT 2A , 5HT 2C , muscarinic M 1 and M 2 , or ␣ 2 adrenergic receptors linked to the PI signaling system or to abnormal levels of substrates, such as PIP 2 , or to components of the signaling cascade, such as G-proteins, PKC, or PLC. Abnormalities in 5HT 2A (Pandey et al. 1995), ␣ 2 adrenergic receptors (Pandey et al. 1990), G-proteins (Garcia-Sevilla et al. 1997Karege et al. 1998;Gurguis et al. 1999), and levels of PIP 2 , a substrate for PI-PLC (Brown et al. 1993;Soares and Mallinger 1996;Soares et al. 1999), have been reported in platelets of unipolar and/or bipolar patients. PLC and PKC are two crucial components of the PI signaling system. Both PKC and PLC have been shown to be involved in a variety of physiological functions, such as synthesis, release, and reuptake of neurotransmitters, neuronal development, transcription, longterm potentiation (LTP), and behavioral responses (Nishizuka 1992). Although the role of PLC in affective disorders has not been fully investigated, some studies have shown abnormalities of PLC in depression and suicide Pandey et al. 1999). On the other hand, very few studies have examined the role of PKC in bipolar or unipolar disorders, although PKC has been implicated in the pathophysiology of bipolar disorders. For example, it has been reported that PKC activity as well as translocation of PKC from cytosol to membrane are increased in platelets of bipolar patients and that lithium treatment alters the activity of PKC in platelets (Friedman et al. 1993;Wang et al. 1999). Further evidence for the involvement of PKC in bipolar disorders is derived from observations that lithium exerts significant effects on PKC in a number of cell systems, including central nervous system (CNS) (Manji et al. 1993(Manji et al. , 1995Manji ...

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Section: Discussionmentioning

confidence: 47%

Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients

Pandey

Dwivedi

SridharaRao

et al. 2002

Neuropsychopharmacology

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“…The ED domain and the flanking N‐terminal sequence are highly conserved among species. Twenty‐five amino acids long and rich in basic amino acids, the ED domain is positively charged and has high electrostatic affinity to the cell membrane and the membrane lipid messenger, phosphatidylinositol 4,5‐bisphosphate (PIP 2 ) 9. MARCKS is known to participate in a variety of signaling pathways, including the protein kinase C (PKC) pathway, that lead to actin cytoskeleton reorganization and increased branched actin polymerization at the cell membrane.…”

Section: Introductionmentioning

confidence: 99%

Myristoylated Alanine‐Rich Protein Kinase Substrate (MARCKS) Regulates Small GTPase Rac1 and Cdc42 Activity and Is a Critical Mediator of Vascular Smooth Muscle Cell Migration in Intimal Hyperplasia Formation

Makkar

Strickland

et al. 2015

JAHA

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BackgroundTranscription of the myristoylated alanine‐rich C kinase substrate (MARCKS) is upregulated in animal models of intimal hyperplasia. MARCKS knockdown inhibits vascular smooth muscle cell (VSMC) migration in vitro; however, the mechanism is as yet unknown. We sought to elucidate the mechanism of MARCKS‐mediated motility and determine whether MARCKS knockdown reduces intimal hyperplasia formation in vivo.Methods and Results MARCKS knockdown blocked platelet‐derived growth factor (PDGF)‐induced translocation of cortactin to the cell cortex, impaired both lamellipodia and filopodia formation, and attenuated motility of human coronary artery smooth muscle cells (CASMCs). Activation of the small GTPases, Rac1 and Cdc42, was prevented by MARCKS knockdown. Phosphorylation of MARCKS resulted in a transient shift of MARCKS from the plasma membrane to the cytosol. MARCKS knockdown significantly decreased membrane‐associated phosphatidylinositol 4,5‐bisphosphate (PIP 2) levels. Cotransfection with an intact, unphosphorylated MARCKS, which has a high binding affinity for PIP 2, restored membrane‐associated PIP 2 levels and was indispensable for activation of Rac1 and Cdc42 and, ultimately, VSMC migration. Overexpression of MARCKS in differentiated VSMCs increased membrane PIP 2 abundance, Rac1 and Cdc42 activity, and cell motility. MARCKS protein was upregulated early in the development of intimal hyperplasia in the murine carotid ligation model. Decreased MARKCS expression, but not total knockdown, attenuated intimal hyperplasia formation.Conclusions MARCKS upregulation increases VSMC motility by activation of Rac1 and Cdc42. These effects are mediated by MARCKS sequestering PIP 2 at the plasma membrane. This study delineates a novel mechanism for MARCKS‐mediated VSMC migration and supports the rational for MARCKS knockdown to prevent intimal hyperplasia.

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Role for the PIP₂‐binding protein myristoylated alanine‐rich C‐kinase substrate in vascular tissue: A novel therapeutic target for cardiovascular disease

Albert,

Jahan,

Greenberg

et al. 2024

Journal of Cell Communication and Signaling

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In vascular smooth muscle cells (VSMCs) and vascular endothelial cells (VECs), phosphatidylinositol 4,5‐bisphosphate (PIP2) acts as a substrate for phospholipase C (PLC)‐ and phosphoinositol 3‐kinase (PI3K)‐mediated signaling pathways and an unmodified ligand at ion channels and other macromolecules, which are key processes in the regulation of cell physiological and pathological phenotypes. It is envisaged that these distinct roles of PIP2 are achieved by PIP2‐binding proteins, which act as PIP2 buffers to produce discrete pools of PIP2 that permits targeted release within the cell. This review discusses evidence for the expression, cell distribution, and role of myristoylated alanine‐rich C‐kinase substrate (MARCKS), a PIP2‐binding protein, in cellular signaling and function of VSMCs. The review indicates the possibilities for MARCKS as a therapeutic target for vascular disease involving dysfunctional cell proliferation and migration, endothelial barrier permeability, and vascular contractility such as atherosclerosis, systemic and pulmonary hypertension, and sepsis.

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The Effector Domain of Myristoylated Alanine-rich C Kinase Substrate Binds Strongly to Phosphatidylinositol 4,5-Bisphosphate

Cited by 171 publications

References 61 publications

Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients

Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients

Myristoylated Alanine‐Rich Protein Kinase Substrate (MARCKS) Regulates Small GTPase Rac1 and Cdc42 Activity and Is a Critical Mediator of Vascular Smooth Muscle Cell Migration in Intimal Hyperplasia Formation

Role for the PIP₂‐binding protein myristoylated alanine‐rich C‐kinase substrate in vascular tissue: A novel therapeutic target for cardiovascular disease

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The Effector Domain of Myristoylated Alanine-rich C Kinase Substrate Binds Strongly to Phosphatidylinositol 4,5-Bisphosphate

Cited by 171 publications

References 61 publications

Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients

Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients

Myristoylated Alanine‐Rich Protein Kinase Substrate (MARCKS) Regulates Small GTPase Rac1 and Cdc42 Activity and Is a Critical Mediator of Vascular Smooth Muscle Cell Migration in Intimal Hyperplasia Formation

Role for the PIP2‐binding protein myristoylated alanine‐rich C‐kinase substrate in vascular tissue: A novel therapeutic target for cardiovascular disease

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Role for the PIP₂‐binding protein myristoylated alanine‐rich C‐kinase substrate in vascular tissue: A novel therapeutic target for cardiovascular disease