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Feedback control of ErbB2 via ERK-mediated phosphorylation of a conserved threonine in the juxtamembrane domain.


ABSTRACT: Tyrosine kinase activity of the asymmetric EGFR homodimer is negatively regulated via ERK-mediated phosphorylation of Thr-669 in the juxtamembrane domain. In the present study, we investigated in human breast cancer cells whether a similar mechanism plays a role in the feedback regulation of the ErbB2/ErbB3 heterodimer, the most potent ErbB receptor dimer. Constitutive tyrosine phosphorylation of ErbB2 and ErbB3 was significantly decreased in phorbol ester- and growth factor-treated BT-474 and MDA-MB-453 cells. In contrast to the decreased tyrosine phosphorylation, Phos-tag Western blot analysis revealed that TPA induced phosphorylation of ErbB2 in an ERK-dependent manner. The target threonine residue corresponding to EGFR Thr-669 and the surrounding residues are highly conserved in ErbB2, but not in ErbB3. Therefore, we demonstrated ERK-mediated phosphorylation of ErbB2 at Thr-677 by generating phospho-specific monoclonal antibodies. Moreover, treatment with trametinib and SCH772984, inhibitors of the MEK-ERK pathway, and substitution of Thr-677 to alanine impaired the feedback inhibition of ErbB2 and ErbB3. These results demonstrated that ERK-mediated phosphorylation of the conserved threonine is a common mechanism for the negative feedback control of active ErbB receptor dimers.

SUBMITTER: Kawasaki Y 

PROVIDER: S-EPMC4987620 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Feedback control of ErbB2 via ERK-mediated phosphorylation of a conserved threonine in the juxtamembrane domain.

Kawasaki Yuki Y   Sakimura Ayaka A   Park Chul Min CM   Tomaru Rika R   Tanaka Tomohiro T   Ozawa Tatsuhiko T   Zhou Yue Y   Narita Kaori K   Kishi Hiroyuki H   Muraguchi Atsushi A   Sakurai Hiroaki H  

Scientific reports 20160817


Tyrosine kinase activity of the asymmetric EGFR homodimer is negatively regulated via ERK-mediated phosphorylation of Thr-669 in the juxtamembrane domain. In the present study, we investigated in human breast cancer cells whether a similar mechanism plays a role in the feedback regulation of the ErbB2/ErbB3 heterodimer, the most potent ErbB receptor dimer. Constitutive tyrosine phosphorylation of ErbB2 and ErbB3 was significantly decreased in phorbol ester- and growth factor-treated BT-474 and M  ...[more]

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