The human epidermal growth factor receptor contains a juxtamembrane calmodulin-binding site

Biochemistry
J Martín-Nieto, Antonio Villalobo

Abstract

A ligand-insensitive form of the human epidermal growth factor receptor (EGFR) was enriched by Ca2+-dependent calmodulin-affinity chromatography purification. The basic amphiphilic segment Arg645-Arg-Arg-His-Ile-Val-Arg-Lys-Arg-Thr654-Leu-Arg-Arg-Le u-Leu-Gln 660, located within the cytoplasmic juxtamembrane domain of this receptor, was purified as a fusion protein with glutathione S-transferase and shown to bind calmodulin in a Ca2+-dependent manner. An apparent dissociation constant of 0.4 microM calmodulin (Kd'(CaM)) and an apparent affinity constant of 0.5 microM free Ca2+ (Ka'(Ca)) were measured for this binding process. Binding of calmodulin at the juxtamembrane site prevented the phosphorylation of residue Thr-654 by protein kinase C, and an apparent inhibition constant of 0.5-1 microM calmodulin (Ki'(CaM)) was determined. Conversely, phosphorylation of this site by protein kinase C prevented its subsequent interaction with calmodulin. We therefore propose that cross talk between signaling pathways mediated by calmodulin and protein kinase C occurs at the juxtamembrane domain of the EGFR. This calmodulin-binding sequence is highly conserved among protein tyrosine kinases of the vertebrate EGFR family.

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