The Epidermal Growth Factor Receptor and the Calcium Signal

Villalobo, Antonio; Ruano, Marı́a José; Palomo-Jiménez, Paloma I.; Li, Hongbing; Martı́n-Nieto, José

doi:10.1007/978-94-010-0688-0_18

Cited by 12 publications

(18 citation statements)

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“…(i) In the absence of ligand the EGFR is auto-inhibited; (ii) upon EGF stimulation, the low cytosolic concentration of free Ca 2 + initially prevailing under such conditions [57] could favour an ultra-fast phosphorylation of apo-CaM by the EGFR [17,18,33,34], particularly if CaM were to be already tethered to the receptor; (iii) the generated P-(Tyr)-CaM could help to partially activate the EGFR, initiating the generation of the Ca 2 + signal; (iv) as the cytosolic concentration of free Ca 2 + rises [56], additional phosphorylation of CaM should come to a halt [17,18,33,34]; and (v) the increase in the cytosolic concentration of free Ca 2 + would induce the formation of the Ca 2 + -CaM and/or Ca 2 + /P-(Tyr)-CaM complexes allowing the complete detachment of the CaM-BD of the EGFR from the inner leaflet of the plasma membrane according to the model proposed by McLaughlin et al [25], thereby maintaining the receptor in a fully active state.…”

Section: Discussionmentioning

confidence: 99%

The activating role of phospho-(Tyr)-calmodulin on the epidermal growth factor receptor

Stateva

Salas

Benguría

et al. 2015

Biochemical Journal

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The activity of calmodulin (CaM) is modulated not only by oscillations in the cytosolic concentration of free Ca 2 + , but also by its phosphorylation status. In the present study, the role of tyrosine-phosphorylated CaM [P-(Tyr)-CaM] on the regulation of the epidermal growth factor receptor (EGFR) has been examined using in vitro assay systems. We show that phosphorylation of CaM by rat liver solubilized EGFR leads to a dramatic increase in the subsequent phosphorylation of poly-L-(Glu:Tyr) (PGT) by the receptor in the presence of ligand, both in the absence and in the presence of Ca 2 + . This occurred in contrast with assays where P-(Tyr)-CaM accumulation was prevented by the presence of Ca 2 + , absence of a basic cofactor required for CaM phosphorylation and/or absence of CaM itself. Moreover, an antibody against CaM, which inhibits its phosphorylation, prevented the extra ligand-dependent EGFR activation. Addition of purified P-(Tyr)-CaM, phosphorylated by recombinant c-Src (cellular sarcoma kinase) and free of non-phosphorylated CaM, obtained by affinity-chromatography using an immobilized antiphospho-(Tyr)-antibody, also increased the ligand-dependent tyrosine kinase activity of the isolated EGFR toward PGT. Also a CaM(Y99D/Y138D) mutant mimicked the effect of P-(Tyr)-CaM on ligand-dependent EGFR activation. Finally, we demonstrate that P-(Tyr)-CaM binds to the same site (as non-phosphorylated CaM, located at the cytosolic juxtamembrane region of the EGFR. These results show that P-(Tyr)-CaM is an activator of the EGFR and suggest that it could contribute to the CaM-mediated ligand-dependent activation of the receptor that we previously reported in living cells.

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Section: Discussionmentioning

confidence: 99%

The activating role of phospho-(Tyr)-calmodulin on the epidermal growth factor receptor

Stateva

Salas

Benguría

et al. 2015

Biochemical Journal

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“…The activation of the EGFR generates a Ca 2+ signal, broadly defined as the transient rise of the intracellular concentration of Ca 2+ . This is followed by the formation of the Ca 2+ /CaM complex and the initiation of elaborated mechanisms pertaining to the control of the receptor at multiple levels [21,22].…”

Section: The Ca2+ Signal Generated By the Egfrmentioning

confidence: 99%

Calmodulin‐mediated regulation of the epidermal growth factor receptor

2010

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In this review, we first describe the mechanisms by which the epidermal growth factor receptor generates a Ca2+ signal and, subsequently, we compile the available experimental evidence regarding the role that the Ca2+/calmodulin complex, formed after the rise in cytosolic free Ca2+ concentration, exerts on the receptor. We focus not only on the indirect action that Ca2+/calmodulin exerts on the epidermal growth factor receptor, as a result of the activation of distinct calmodulin‐dependent kinases, but also, and more extensively, on the direct interaction of Ca2+/calmodulin with the receptor. We also describe several mechanistic models that could account for the Ca2+/calmodulin‐mediated regulation of epidermal growth factor receptor activity. The control exerted by calmodulin on distinct epidermal growth factor receptor‐mediated cellular functions is also discussed. Finally, the phosphorylation of this Ca2+ sensor by the epidermal growth factor receptor is highlighted.

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“…The effect of CaM phosphorylated by the EGFR on the tyrosine kinase activity of this receptor has been studied in a preliminary manner. The results indicate that this P‐(Tyr)‐CaM species could be an activator of the tyrosine kinase activity of the receptor both in the presence and absence of Ca 2+ [53,59,75], while nonphosphorylated CaM has an inhibitory effect only in the presence of Ca 2+ [52,55] (Table 2). The space‐temporal phases on which CaM and P‐(Tyr)‐CaM interact with the EGFR in intact cells have not yet been identified.…”

Section: Functional Implications For the Differential Modulation Of Cmentioning

confidence: 99%

Phosphorylation of calmodulin

Benaím

Villalobo

2002

European Journal of Biochemistry

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134

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Calmodulin (CaM) is phosphorylated in vitro and in vivo by multiple protein-serine/threonine and protein-tyrosine kinases. Casein kinase II and myosin light-chain kinase are two of the well established protein-serine/threonine kinases implicated in this process. On the other hand, within the protein-tyrosine kinases involved in the phosphorylation of CaM are receptors with tyrosine kinase activity, such as the insulin receptor and the epidermal growth factor receptor, and nonreceptor protein-tyrosine kinases, such as several members of the Src family kinases, Janus kinase 2, and p38Syk. The phosphorylation of CaM brings important physiological consequences for the cell as the diverse phosphocalmodulin species have differential actions as compared to nonphosphorylated CaM when acting on different CaM-dependent systems. In this review we will summarize the progress made on this topic as the first report on phosphorylation of CaM was published almost two decades ago. We will emphasize the description of the phosphorylation events mediated by the different protein kinases not only in the test tube but in intact cells, the phosphorylation-mediated changes of CaM activity, its action on CaM-dependent systems, and the functional repercussion of these phosphorylation processes in the physiology of the cell.Keywords: calmodulin; calmodulin-dependent systems; cellular signalling; phosphocalmodulin; protein kinases; phosphoprotein phosphatases. I N T R O D U C T I O N Calmodulin as a Ca 2+ sensorThe average cytosolic concentration of free Ca 2+ in resting cells ranges from 20 to 50 nM, reaching values close to 1 lM when the cell is stimulated by a variety of physiological stimuli, while in the extracellular milieu this concentration is about 1 mM. This large concentration gradient allows intracellular Ca 2+ to work as an useful second messenger [1,2]. The cytosolic Ca 2+ concentration is exquisitely regulated by the operation of transport systems responsible for its increase, represented by different types of Ca 2+ channels and Na + (H + )/Ca 2+ exchangers located in the plasma membrane, the endo(sarco)plasmic reticulum, and/or the mitochondria; and extrusion transport systems represented by Ca 2+ -ATPases located in both the plasma membrane and the endo(sarco)plasmic reticulum, and the Na + /Ca 2+ exchanger also located within the plasma membrane [1,3]. The operation of theses transporters gives rise to oscillations in the concentration of Ca 2+ not only in the cytosol but in the nucleus and intracellular organelles [1,4,5]. It has been possible to observe in living cells inhomogeneities in these transient changes inCorrespondence to A. Villalobo, Instituto de Investigaciones Biome´dicas, Consejo Superior de Investigaciones Cientı´ficas and Universidad Auto´noma de Madrid, Arturo Duperier 4, E-28029 Madrid, Spain. E-mail: antonio.villalobo@iib.uam.es Abbreviations: AdeCycl, adenylate cyclase; CaM, calmodulin; CaM-BD, calmodulin-binding domain; CaMPK-II, calmodulin-dependent protein kinase II; CK-II, casein kinase II; CKR,...

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The Epidermal Growth Factor Receptor and the Calcium Signal

Cited by 12 publications

References 78 publications

The activating role of phospho-(Tyr)-calmodulin on the epidermal growth factor receptor

The activating role of phospho-(Tyr)-calmodulin on the epidermal growth factor receptor

Calmodulin‐mediated regulation of the epidermal growth factor receptor

Phosphorylation of calmodulin

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