Calmodulin‐mediated regulation of the epidermal growth factor receptor

Abstract

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.

MAPK Scaffold IQGAP1 Binds the EGF Receptor and Modulates Its Activation

“…brane region of the receptor (residues 645-660) (49 We did not find any evidence for IQGAP1 phosphorylation on tyrosine residues, either by mass spectrometry or Western blot analysis. Using unbiased mass spectrometry techniques that detect phosphorylation on serine, threonine, and tyrosine equally, we found that only Ser 1443 was activated in response to EGF (data not shown).…”

“…Because the IQ domains are necessary for EGFR to bind IQGAP1, it is reasonable to postulate that the presence of Ca 2ϩ /calmodulin in the IQ domains blocks access to EGFR binding. In contrast to most other IQGAP1 binding partners, EGFR also binds calmodulin directly (49), and Ca 2ϩ is required for calmodulin to bind to the EGFR at the juxtamem- , and PKCe, respectively) or ␣ and ⑀ together (PKCa-e). After overnight serum starvation, cells were treated with either vehicle (Ϫ) or 100 ng/ml EGF (ϩ) for 5 min.…”

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

“…To integrate within a physiological framework the transient EGF-dependent Ca 2 + signal generated by the receptor [27,56] with the positive regulatory effect of P-(Tyr)-CaM on the EGFdependent EGFR activation (the present work), we propose a hypothetical CaM/P-(Tyr)-CaM regulatory cycle whose main steps could be described as follows ( Figure 6). (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.…”

“…Likewise, ErbB2 also interacts with Ca 2 + -CaM regulating downstream signalling [26]. Different mechanistic models have been proposed to account for the stimulatory action of Ca 2 + -CaM on EGFR activation [27]. The most likely mechanism involves the Ca 2 + -CaM-induced release of the positively-charged CaM-BD from the phosphoinositiderich negatively-charged inner leaflet of the plasma membrane, an electrostatic interaction which otherwise would maintain the ligand-free receptor auto-inhibited [22,25,28].…”

Germinal center kinases in immune regulation

“…82 Meanwhile, Striatin can also bind to calmodulin (a calcium-binding protein that regulates the functions of many kinases), phosphotases, ion channels and other proteins in a calcium-dependent manner. [83][84][85] We have postulated that PDCD10 may cross-talk with FAK. …”