Crosstalk of the EphA2 receptor with a serine/threonine phosphatase suppresses the Akt-mTORC1 pathway in cancer cells

Abstract

Receptor tyrosine kinases of the Eph family play multiple roles in the physiological regulation of tissue homeostasis and in the pathogenesis of various diseases, including cancer. The EphA2 receptor is highly expressed in most cancer cell types, where it has disparate activities that are not well understood. It has been reported that interplay of EphA2 with oncogenic signaling pathways promotes cancer cell malignancy independently of ephrin ligand binding and receptor kinase activity. In contrast, stimulation of EphA2 signaling with ephrin-A ligands can suppress malignancy by inhibiting the Ras-MAP kinase pathway, integrin-mediated adhesion, and epithelial to mesenchymal transition. Here we show that ephrin-A1 ligand-dependent activation of EphA2 decreases the growth of PC3 prostate cancer cells and profoundly inhibits the Akt-mTORC1 pathway, which is hyperactivated due to loss of the PTEN tumor suppressor. Our results do not implicate changes in the activity of Akt upstream regulators (such as Ras family GTPases, PI3 kinase, integrins, or the Ship2 lipid phosphatase) in the observed loss of Akt T308 and S473 phosphorylation downstream of EphA2. Indeed, EphA2 can inhibit Akt phosphorylation induced by oncogenic mutations of not only PTEN but also PI3 kinase. Furthermore, it can decrease the hyperphosphorylation induced by constitutive membrane-targeting of Akt. Our data suggest a novel signaling mechanism whereby EphA2 inactivates the Akt-mTORC1 oncogenic pathway through Akt dephosphorylation mediated Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

Cooperative Signaling between Slit2 and Ephrin-A1 Regulates a Balance between Angiogenesis and Angiostasis

“…(52), which could in turn impair downstream activation of Akt and/or Rac. Alternatively, ephrin-A1 could activate a serine/ threonine phosphatase, which could inhibit Akt and/or mTOR function, as recently described by Yang et al (74). Further investigation is required to identify the precise target of inhibition.…”

Irradiation affects cellular properties and Eph receptor expression in human melanoma cells

“…36 EphA2 activation also decreased proliferation in breast cancer cells and in prostate carcinoma cells by inhibiting phosphorylation of serine/threonine protein kinase Akt. 37,38 On the other hand, it was demonstrated that the expression of EphA2 is associated with increased tumor cell proliferation in cutaneous melanoma. 39 The influence of EphA2 activation on the cytoskeleton and, hence, on adhesion, migration and metastasis is under intensive investigation and several involved signaling pathways have been identified so far.…”

Emerging and Diverse Functions of the EphA2 Noncanonical Pathway in Cancer Progression

“…[1][2][3][4][5][6][9][10][11][12][13][14][15][17][18][19]37,38) Of note, in some types of cells, the canonical pathway was reported to promote ERK activation via SH2-coutaining collagen-related proteins (SHC) and growth factor receptor-bound protein 2 (GRB2). 39) This disparity highlights how the cell type and cell microenvironment affect signaling.…”