Ca2+–calmodulin and protein kinase Cs: a hypothetical synthesis of their conflicting convergences on shared substrate domains

K-Ras4B phosphorylation at Ser181 is inhibited by calmodulin and modulates K-Ras activity and function

“…The fact that CaM inhibits K-Ras phosphorylation is not surprising as Ser181 is found within one of the CaMbinding domains of K-Ras, and probably CaM can hide the phosphorylation site. This regulatory mechanism has already been shown for other CaM-binding proteins, such as neurogranin, neuromodulin, myristylated alanine-rich C-kinase substrate (Chakravarthy et al, 1999) and p21 (Rodriguez-Vilarrupla et al, 2005;Agell et al, 2006). In analogy to other CaM-binding proteins, phosphorylation within the CaM-binding region of K-Ras inhibits its binding to CaM (Lopez-Alcala et al, 2008).…”

Stimulation of cleavage of membrane proteins by calmodulin inhibitors

“…First, CaM acts as a cellular intermediate of multiple Ca# + actions, and changes in intracellular Ca# + have been reported to regulate the cleavage of several membrane proteins [1]. Secondly, CaM has been shown to interfere with the PKC pathway by embedding of PKC phosphorylation sites on substrates in CaM crypts [26]. Finally, a recent report suggested a role of CaM in the release of soluble L-selectin, probably by direct interaction of CaM with the cytosolic domain of the adhesion molecule [27].…”

“…Evidence accumulated during the last few years indicates that CaM and PKC have opposite actions because of the embedding of PKC phosphorylation sites in CaM-binding domains [26]. Thus it was of interest to elucidate whether CaM inhibitors acted by releasing a substrate that participated in the regulation of membrane-protein ectodomain cleavage, and was activated by PKC.…”

“…Since a direct relationship between these pathways and CaM exists [26], the question of whether the action of CaM inhibitors could be mediated by any of the above second messenger routes was analysed. As a preliminary step, and since TrkA cleavage in response to Ca# + agonists has not been reported, the action of agents that increase intracellular free Ca# + concentration on TrkA cleavage was investigated.…”

“…An important intracellular mediator in the actions of Ca# + is calmodulin (CaM) [24][25][26]. Recently, CaM was shown to be involved in the regulation of the shedding of the adhesion molecule L-selectin [27].…”