Activation of the EphA2 tyrosine kinase stimulates the MAP/ERK kinase signaling cascade

Abstract

Intracellular signaling by receptor tyrosine kinases regulates many different aspects of cell behavior. Recent studies in our laboratory and others have demonstrated that the EphA2 receptor tyrosine kinase critically regulates tumor cell growth, migration and invasiveness. Although the cellular consequences of EphA2 signaling have been the focus of recent attention, the biochemical changes that are triggered by ligand-mediated activation of EphA2 remain largely unknown. Herein, we demonstrate that ligand stimulation of EphA2 promotes the nucleus translocation and phosphorylation of ERK kinases, followed by an increase in nuclear induction of the Elk-1 transcription factor. Ligand-mediated activation allows EphA2 to form a molecular complex with the SHC and GRB2 adaptor proteins. Specifically, we demonstrate that tyrosine phosphorylated EphA2 interacts with the PTB and SH2 domains of SHC. We also show that the interaction of EphA2 with GRB2 is indirect and mediated by SHC and that this complex is necessary for EphA2-mediated activation of ERK kinases. These studies provide a novel mechanism to demonstrate how EphA2 can convey information from the cell exterior to the nucleus.

Protein vaccination with HPV16 E7/Pep‐1 nanoparticles elicits a protective T‐helper cell‐mediated immune response

“…The studies indicated that regression of tumor depends on stimulation of a CD41 T cell-dominated Th1 response. Up to now, Pep-1-based formulations have shown to be an excellent technology for antibody transduction in primary neurons and to be able to cross the blood-brain barrier (21,22,41,42). Recently, Pep-1 strategy has been used to deliver caspase 3 into the lung of mice to generate alveolar wall apoptosis or to repair a defective step in a cellular signaling pathway.…”

Differential Regulation of EphA2 in Normal and Malignant Cells

“…26,54 In addition, tyrosine-phosphorylated EphA2 interacts with SHC, which in turn binds GRB2 to stimulate intracellular signaling and nuclear translocation of ERK kinases. 61 In doing so, EphA2 rapidly translates signals from the cell surface to the nucleus. 61 At first glance, these results seem to contradict a published study, which showed decreased ERK activity following Eph kinase stimulation.…”

“…These interactions include binding to Shc, Grb2, SHP-2 SLAP, and PI 3-kinase. 26,52,54,61,64 The downstream consequences of these interactions include direct induction of the enzymatic activities of PI 3-kinase and SHP-2. 26,54 In addition, tyrosine-phosphorylated EphA2 interacts with SHC, which in turn binds GRB2 to stimulate intracellular signaling and nuclear translocation of ERK kinases.…”

Immunocompetent mouse model of breast cancer for preclinical testing of EphA2-targeted therapy

“…This binding leads to autophosphorylation of three tyrosine residues present in the intracytoplasmic domain of EphA2 [3][4][5][6] and then activates or inhibits other kinases before getting internalized and degraded. [7][8][9] Functionally altered EphA2 in invasive human breast cancer cells fails to bind to its ligand EphrinA1 leading to the accumulation of unphosphorylated EphA2. 1 The purified secretory form of EphrinA1 (EphrinA1-Fc) protein 1 or EphrinA1-Fc expressed by an adenoviral vector 10 has been shown to activate EphA2 in breast cancer cells resulting in inhibition of their tumorigenic potential.…”