Protein kinase A can block EphA2 receptor–mediated cell repulsion by increasing EphA2 S897 phosphorylation

Abstract

The EphA2 receptor plays multiple roles in cancer through two distinct signaling mechanisms. In a novel cross-talk, the β2-adrenoceptor/cAMP/PKA axis can promote EphA2 pro-oncogenic, ligand-independent signaling, blocking cell repulsion induced by ligand-dependent signaling. PKA emerges as a third kinase, besides AKT and RSK, that can regulate EphA2.

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

“…A recent report has shown that EphA2 Ser-897 can be phosphorylated by protein kinase A (PKA), but not by Akt, in forskolin-stimulated prostate cancer cells. 46) PKA also belongs to the AGC family and has a similar substrate recognition motif, suggesting that other AGC protein kinases may catalyze EphA2 Ser-897. It was also shown that not all prostate and pancreatic cancer cell lines, which those authors used in their experiments, 46) were sensitive to forskolin.…”

“…46) PKA also belongs to the AGC family and has a similar substrate recognition motif, suggesting that other AGC protein kinases may catalyze EphA2 Ser-897. It was also shown that not all prostate and pancreatic cancer cell lines, which those authors used in their experiments, 46) were sensitive to forskolin. However, EGF-induced phosphorylation of EphA2 on Ser-897 was detected in all cell lines, suggesting that the cellular context and cell environment influence the kinase of EphA2 Ser-897.…”

“…46) Ser-901 is also located in the same linker region, and there are three other serine/threonine phosphorylation sites. This region should play a main role in EphA2 noncanonical activation, and therefore a detailed study of the five phosphorylation sites will be important to understand EphA2 noncanonical regulation fully.…”

“…Barquilla et al 46) determined that PKA-EphA2 signaling inhibits cell retraction, a prototypical repulsive response. Retraction was induced by ephrin-A1 stimulation in a prostate cancer cell line, and forskolin or PKA agonist inhibited cell retraction via EphA2 phosphorylation at Ser-892, -897, and -901, suggesting that other phosphorylation sites located in the linker region also contribute to the EphA2 noncanonical pathway.…”

“…Retraction was induced by ephrin-A1 stimulation in a prostate cancer cell line, and forskolin or PKA agonist inhibited cell retraction via EphA2 phosphorylation at Ser-892, -897, and -901, suggesting that other phosphorylation sites located in the linker region also contribute to the EphA2 noncanonical pathway. 46) Not only in cancer cells but also in normal cells, cell motility depends on the noncanonical signaling pathway. Wiedemann et al reported that ephrin-A1 expression was decreased in low-density HUVEC cultures in which EphA2 Ser-897 instead of Tyr-588 was phosphorylated to regulate cell motility and proliferation.…”