Functional Interaction of Calcium-/Calmodulin-dependent Protein Kinase II and Cytosolic Phospholipase A2

Abstract

on Ser-515, but not on Ser-505 or Ser-727, occurs in vivo. This novel signaling pathway for arachidonate release is shown to be cPLA 2 -dependent by use of a recently described and highly selective inhibitor of this enzyme.Many cellular stimuli produce oscillations in the intracellular concentration of Ca 2ϩ . Ca 2ϩ -/calmodulin (CaM) 1 -dependent kinase II (CaM kinase II), a multifunctional protein kinase, decodes the frequency of Ca 2ϩ spikes and regulates the activity of a range of cellular targets involved in many physiological processes including control of cell cycle, apoptosis, gene expression, neurotransmission, synaptic plasticity, learning and memory, and early after-depolarization (1, 2).We have shown previously that the adrenergic transmitter norepinephrine (NE) and angiotensin II increase CaM kinase II activity in vascular smooth muscle cells (VSMC), leading to activation of cytosolic phospholipase A 2 (cPLA 2 ) (3-5). cPLA 2 liberates arachidonic acid by hydrolyzing arachidonyl phospholipids (6, 7). Arachidonic acid is the precursor of a variety of lipid mediators including leukotrienes and prostaglandins that modulate a number of cellular processes (8). cPLA 2 is an attractive target for the development of novel therapies because of its profound role in inflammatory processes, allergic responses, reproductive physiology, post-ischemic brain injury, cell proliferation, and cancer (9 -13).cPLA 2 is activated in a variety of cell types by growth factors, neurotransmitters, angiotensin II, vasopressin, lipopolysaccharides, colony-stimulating factor-1, thrombin, and other agonists (6,14,15). cPLA 2 , like protein kinase C, GTPase-activating proteins, phospholipase C, and p65, contains a Ca 2ϩ -dependent phospholipid binding domain that mediates translocation of cPLA 2 to the nuclear envelope and perinuclear region of cells (16 -18). cPLA 2 is regulated post-translationally by submicromolar Ca 2ϩ and phosphorylation (6, 19). p42/p44 mitogen-activated protein (MAP) kinase phosphorylate cPLA 2 on Ser-505 in many cell types (6, 20), whereas other members of the MAP kinase family, namely p38 stress-activated protein kinases, phosphorylate cPLA 2 in platelets (21). Rigorous studies to map the phosphorylation sites on cPLA 2 have been carried out only with platelets, HeLa cells, and CHO cells, and these studies reveal that cPLA 2 is phosphorylated on . More recent work has shown that Ser-727 phosphorylation is catalyzed by MNK1 or a closely related isoform, which is a protein kinase that is activated by members of the MAP kinase family, and that both Ser-505 and Ser-727 phosphorylation are required for full activation of cPLA 2 (23). In most agonist/cell systems, cPLA 2 phosphorylation is not sufficient for its activation; a rise in intracellular Ca 2ϩ is also required, and Ca 2ϩ -independent cPLA 2 activation by an unknown mechanism has also been reported (6).We reported recently that in VSMC, cPLA 2 -catalyzed arachidonic acid release induced by NE or angiotensin II is significantly reduced by the CaM kinas...

Group VIA Phospholipase A2 Forms a Signaling Complex with the Calcium/Calmodulin-dependent Protein Kinase IIβ Expressed in Pancreatic Islet β-Cells

“…The physiological functions of iPLA 2 ␤ and CaMKII thus appear to be linked in some cells, such as ␤-cells and neurons. Another isoform of CaMKII (CaMKII␣) interacts with Group IVA PLA 2 (cPLA 2 ) in vascular smooth muscle cells (57), and our findings indicate that CaMKII␤ interacts similarly with iPLA 2 ␤ to form a complex. Because ␤-cells express both CaMKII␤ and iPLA 2 ␤, a complex of these enzymes could affect ␤-cell function.…”

Polychlorinated biphenyls induce arachidonic acid release in human platelets in a tamoxifen sensitive manner via activation of group IVA cytosolic phospholipase A2-α

“…Phosphorylation of cPLA 2 -α has been reported in several cell types and on several amino acid residues [26,27]. The role of phosphorylation in membrane association of cPLA 2 -α is unclear but is has been demonstrated that phosphorylation events can, at least partially, contribute to cPLA 2 -α activation [27][28][29][30].…”

“…The role of phosphorylation in membrane association of cPLA 2 -α is unclear but is has been demonstrated that phosphorylation events can, at least partially, contribute to cPLA 2 -α activation [27][28][29][30].…”

Cytosolic Phospholipase A2 Translocates to Forming Phagosomes during Phagocytosis of Zymosan in Macrophages

“…cPLA 2 ␣ is regulated post-translationally by phosphorylation and calcium (15,16). Several functionally important phosphorylation sites in the catalytic domain of cPLA 2 ␣ have been identified (17)(18)(19)(20). Calcium regulates cPLA 2 ␣ by binding the N-terminal C2 domain and inducing translocation from the cytoplasm to Golgi, endoplasmic reticulum (ER), and nuclear membrane (NM) (21)(22)(23)(24).…”