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Título : The activating role of phospho-(Tyr)-calmodulin on the epidermal growth factor receptor
Autor : Stateva, Silviya R.
Salas, Valentina
Benguría, Alberto
Cossío, Itziar
Anguita, Estefanía
Martín-Nieto, José
Benaím, Gustavo
Villalobo, Antonio
Palabras clave : calcium
calmodulin
epidermal growth factor receptor
phospho-(Tyr)-calmodulin
tyrosine kinase
factor receptor
Fecha de publicación : 2015
Editorial : The Biochemical journal
Citación : Vol. 472;No. 2 pp 195–204
Resumen : The activity of calmodulin (CaM) is modulated not only by oscillations in the cytosolic concentration of free Ca2+, 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 Ca2+. This occurred in contrast with assays where P-(Tyr)-CaM accumulation was prevented by the presence of Ca2+, 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 (645R-R-R-H-I-V-R-KR- T-L-R-R-L-L-Q660) 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.
Descripción : To whom correspondence should be addressed (email antonio.villalobo@iib.uam.es).
URI : http://hdl.handle.net/123456789/15703
ISSN : 1470-8728 (Electronic)
0264-6021 (Linking)
0264-6021 (Print)
doi:10.1042/BJ20150851
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