Ligand-independent regulation of ErbB4 receptor phosphorylation by activated Ras

Pazit Tal-Or, Shlomit Erlich, Natalie Porat-Shliom, Yona Goldshmit, Gilad Ben-Baruch, Ezra Shaharabani, Yoel Kloog, Ronit Pinkas-Kramarski

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8 Citations (Scopus)


The ErbB family of receptor tyrosine kinases regulates cell growth, differentiation and survival. Activation of the receptors is induced by specific growth factors in an autocrine, paracrine or juxtacrine manner. The activated ErbB receptors turn on a large variety of signaling cascades, including the prominent Ras-dependent signaling pathways. The activated Ras can induce secretion of growth factors such as EGF and neuregulin, which activate their respective receptors. In the present study, we demonstrate for the first time that activated Ras can activate ErbB4 receptor in a ligand-independent manner. Expression of constitutively active H-Ras(12V), K-Ras(12V) or N-Ras(13V) in PC12-ErbB4 cells induced ErbB4-receptor phosphorylation, indicating that each of the most abundant Ras isoforms can induce receptor activation. NRG-induced phosphorylation of ErbB4 receptor was blocked by the soluble ErbB4 receptor, which had no effect on the Ras-induced receptor phosphorylation. Moreover, conditioned medium from H-Ras(12V)-transfected PC12-ErbB4 cells had no effect on receptor phosphorylation. It thus indicates that Ras induces ErbB4 phosphorylation in a ligand-independent manner. Each of the Ras effector domain mutants, H-Ras(12V)S35, H-Ras(12V)C40, and H-Ras(12V)G37, which respectively activate Raf1, PI3K...
Original languageEnglish
Pages (from-to)1482 - 1494
Number of pages13
JournalJournal of Cellular Biochemistry
Issue number6
Publication statusPublished - 2006
Externally publishedYes

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