|Title:||Regulation of EGF receptor activation by phosphohistidine phosphatase PHPT1|
|Abstract:||Phosphorylation of polybasic stretches in membrane-associated proteins creates an electrostatic switch influencing their interactions with membrane lipids. Such modification affects their localization, conformational fluctuations and ultimately function. One example for this is the epidermal growth factor receptor (EGFR), which is involved in the pathogenesis of many cancers. EGFR activation is coupled to a conformational change, where the intracellular domain is released from an autoinhibitory interaction with the plasma membrane after ligand induced calmodulin (CaM) binding. The CaM dependent receptor activation occurs in analogy to the ion channel KCa3.1, which is regulated via histidine phosphorylation. Histidine (His358) phosphorylation of the KCa3.1 channel by nucleoside diphosphate kinase B (NME2) induces binding of the active calcium-CaM complex and further activation, while dephosphorylation by phosphohistidine phosphatase 1 (PHPT1) results in an inactive conformation. For EGFR, a single histidine residue (His648), located in the polybasic CaM binding domain (BD), may act as a possible regulatory site. This study demonstrates that the His648 residue is essential for intact ligand induced EGFR activation. For the first time, PHPT1 is identified as a new key player in regulating EGFR activation. Transient PHPT1 overexpression amplifies Tyr phosphorylation of spontaneously activated EGFR, whereas the ligand induced EGFR phosphorylation is reduced. The previously identified oncogenic propensities of PHPT1 could be explained by its enhancement of spontaneous EGFR activation. In addition, the phosphohistidine kinases NME1 and NME2 show the opposite effect in regulating EGFR activation, indicative for a regulation of EGFR activation by the phosphohistidine phosphatase/kinase system in vertebrates. Furthermore, the results suggest that PHPT1 modulates receptor activation in absence and presence of ligand in two independent mechanisms.|
|Subject Headings:||EGFR Activation|
|Appears in Collections:||Chemische Biologie|
Files in This Item:
|PhDThesis_JuliaWernicke_31052017.pdf||DNB||13.15 MB||Adobe PDF||View/Open|
This item is protected by original copyright
All resources in the repository are protected by copyright.