Calmodulin requiring protein kinases

LiuD, MatzukMM, Sung WK, Guo Q, WangP, Wolgemuth DJ 1998 Cyclin A1 is required for meiosis in the male mouse. Nat Genet 20 377-380 Lorca T, Cruzalequi FH, Fesquet D et al 1993 Calmodulin-dependent protein kinase II mediates inactivation of MPF and CSF activities upon fertilization of Xenopus eggs. Nature 366 270-273... 

FIGURE 1 2-2 Schematic diagram of the phosphorylation sites on each of the four 60kDa subunits of tyrosine hydroxylase (TOHase). Serine residues at the N-terminus of each of the four subunits of TOHase can be phosphorylated by at least five protein kinases. (J), Calcium/calmodulin-dependent protein kinase II (CaM KII) phosphorylates serine residue 19 and to a lesser extent serine 40. (2), cAMP-dependent protein kinase (PKA) phosphorylates serine residue 40. (3), Calcium/phosphatidylserine-activated protein kinase (PKC) phosphorylates serine 40. (4), Extracellular receptor-activated protein kinase (ERK) phosphorylates serine 31. (5), A cdc-like protein kinase phosphorylates serine 8. Phosphorylation on either serine 19 or 40 increases the activity of TOHase. Serine 19 phosphorylation requires the presence of an activator protein , also known as 14-3-3 protein, for the expression of increased activity. Phosphorylation of serines 8 and 31 has little effect on catalytic activity. The model shown includes the activation of ERK by an ERK kinase. The ERK kinase is activated by phosphorylation by PKC. (With permission from reference [72].)... 

The synthesis of 5-HT can increase markedly under conditions requiring more neurotransmitter. Plasticity is an important concept in neurobiology. In general, this refers to the ability of neuronal systems to conform to either short- or long-term demands placed upon their activity or function (see Plasticity in Ch. 53). One of the processes contributing to neuronal plasticity is the ability to increase the rate of neurotransmitter synthesis and release in response to increased neuronal activity. Serotonergic neurons have this capability the synthesis of 5-HT from tryptophan is increased in a frequency-dependent manner in response to electrical stimulation of serotonergic soma [7]. The increase in synthesis results from the enhanced conversion of tryptophan to 5-HTP and is dependent on extracellular calcium ion. It is likely that the increased 5-HT synthesis results in part from alterations in the kinetic properties of tryptophan hydroxylase, perhaps due to calcium-dependent phosphorylation of the enzyme by calmodulin-dependent protein kinase II or cAMP-dependent protein kinase (PKA see Ch. 23). 

This enzyme [EC 2.7.1.123], also referred to as calcium/ calmodulin-dependent protein kinase type II, and micro-tubule-associated protein MAP2 kinase, catalyzes the reaction of ATP with a protein to produce ADP and an 0-phosphoprotein. The enzyme requires calcium ions and calmodulin. Proteins that can serve as substrates include vimentin, synapsin, glycogen synthase, the myosin light-chains, and the microtubule-associated tau protein. This enzyme is distinct from myosin light-chain kinase [EC 2.7.1.117], caldesmon kinase [EC 2.7.1.120], and tau-protein kinase [EC 2.7.1.135]. 

Chow, F. A., Anderson, K. A., Noeldner, P. K. and Means, A. R., 2005, The autonomous activity of calcium/calmodulin-dependent protein kinase IV is required for its role in transcription, J Biol Chem, 280, pp 20530-8. 

It was originally recognised by Dabrowska et al. (1978) that calmodulin was part of the active holoenzyme MLCK complex. The association of calmodulin with MLCK is rapid and appears to be diffusion limited. It could be described by a two-step process, a bimolecular step and an isomerisation (Torok and Trentham 1994). The time required for activating MLCK by Ca +/calmodulin may contribute to the latency of about 400-500 ms at 37 C which precedes increases in LC20 phosphorylation (Miller-Hance et al. 1988). The interaction of Ca Vcalmodulin with MLCK may be modulated by phosphorylation of MLCK. Purified MLCK is a substrate for protein kinase A (Conti and Adelstein 1981), the multifunctional Ca /calmodulin dependent protein kinase II (Hashimoto and Soderling 1990, Ikebe and Reardon 1990), protein kinase C (PKC) (Nishikawa et al. 1983) and mitogen activated protein kinase (MAP kinase, Klemke et al. 1997). Phosphorylation of MLCK by these protein kinases may alter the Ca -sensitivity of the enzyme and hence of contraction, as will be discussed below. 

This study served to verify our previous report (2) that phospholipase activity in potato leaves is stimulated by protein phosphorylation and by calmodulin. More importantly, it demonstrated that the degree of stimulation of the same enzyme activity by proteolytic activation was even greater than the degree of stimulation with protein kinase or calmodulin. Further work is required in order to elucidate the mechanisms of these three types of stimulation. We previously suggested that the calmodulin and protein kinase stimulations could be explained by phosphorylation of a phospholipase enzyme by an endogenous calmodulin-stimulated protein kinase (2). However, in light of the current evidence of proteolytic activation, a more complex mechanism of activation is necessary to best explain the three types of activation. 

Lead also has been shown to substitute for calcium in the activation of calmodulin, but this requires higher levels of lead than does the activation of protein kinase C. Nevertheless, the affinity of lead for calmodulin is higher than that of calcium. Once activated, calmodulin regulates the activity of certain enzymes and transporters. For example, it activates c-AMP phosphodiesterase to hydrolyze and terminate the action of cAMP, another second messenger (Bressler and Goldstein 1991 Goldstein 1993 Goering 1993). 

DG). InsP3, as we saw above, stimulates the release of Ca2+, sequestered in the ER, and this in turn activates numerous cellular processes through Ca2+-binding proteins, such as calmodulin. The membrane-associated DG activates protein kinase C to phosphorylate and activate other enzymes, such as glycogen phosphorylase. This step also requires Ca2+. 

The diacylglycerols released by phospholipase C diffuse laterally through the bilayer and, together with the incoming Ca2+, activate protein kinases C. These kinases also require phosphatidylserine for their activity and phosphorylate serine and threonine side chains in a variety of proteins.329 330b They are stimulated by the released unsaturated diacylglycerols. In addition protein kinases C can be activated by phorbol esters, which are the best known tumor promoters (Box 11-D). The diacylglycerol requirement favors a function for these protein kinases in membranes. They also appear to cooperate with calmodulin to activate the Ca2+-dependent contraction of smooth muscle.330... 

Eguchi, S., Matsumoto, T., Motley, E. D., et al. 1996. Identification of an essential signaling cascade for mitogen-activated protein kinase activation by angiotensin II in cultured rat vascular smooth muscle cells. Possible requirement of Gq-mediated p21ras activation coupled to a Ca2+/calmodulin-sensitive tyrosine kinase. J Biol Chem 271 14169-14175. 

Phosphorylase kinase is one of the best characterized enzyme systems to illustrate the role of calcium ions in regulation of intermediary metabolism. Phosphorylase kinase is composed of four different subunits termed a (Mr 145000), /3 (MT 128000), y (A/r 45000) and 5 (Mr 17000) and has the structure (a/3y8)A [106]. Only one of its four subunits actually catalyses the phosphorylation reaction the other three subunits are regulatory and enable the enzyme complex to be activated both by calcium and cyclic AMP. The y subunit carries the catalytic activity the 8 subunit is the calcium binding protein calmodulin and is responsible for the calcium dependence of the enzyme. The a and /3 subunits are the targets for cyclic-AMP mediated regulation, both being phosphorylated by the cyclic-AMP dependent protein kinase. Calmodulin appears to interact with phosphorylase kinase in a different manner from other enzymes, since it is an integral component of the enzyme. Phosphorylase kinase has an absolute requirement for calcium, and is inactive in its absence. 

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