Basal and Src kinase‐mediated activation of the EphA2 promoter requires a cAMP‐responsive element but is CREB‐independent

Abstract

We have previously identified the EphA2 receptor tyrosine kinase as a potentially important injury-responsive gene and a transcriptional target of Src kinase activity in renal ischemia-reperfusion injury (IRI). In the present study, we confirmed, using EphA2 gene trap mice that the endogenous EphA2 promoter is strongly activated following renal IRI. We also examined in more detail the mechanisms responsible for Src kinase-induced activation of the -2 kb human EphA2 promoter and found that the minimal Src-responsive elements were contained in the -145 to +137 region of the human EphA2 gene. This region contains a canonical cAMP-responsive element (CRE) that we found to be critical for both basal and Src kinase-induced transcriptional activity. However, despite activation of the prototypical CRE-binding factor CREB by the Src kinase Fyn, siRNA-mediated knockdown of CREB had no significant impact on either basal or Fyn-induced EphA2 promoter activity. Similarly, activation of CREB by the adenylate cyclase agonist forskolin failed to induce EphA2 promoter activation. Thus, Src kinase-induced activation of the EphA2 promoter is CRE-dependent but CREB-independent.

EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer

“…Given its potential role in CRC progression and metastasis, we further investigated how EphA2 expression levels are regulated in CRC. In contrast to previous studies, our data did not show a role for p53 or the Src Family Kinases in regulating EphA2 expression (44, 45). Using a systems biology approach, we previously identified EphA2 as a potential KRAS target in KRAS MT CRC cells (15).…”

Cytosolic Phospholipase A2α and Eicosanoids Regulate Expression of Genes in Macrophages Involved in Host Defense and Inflammation

“…These include the Eph receptor A2 tyrosine kinase ( EphA2 , Vascular development cluster), the epidermal growth factor receptor (EGFR) ligands epiregulin ( Ereg ) and amphiregulin ( Areg ) (Growth factor cluster), the transmembrane glycoprotein podoplanin ( Pdpn ) and its transcriptional regulator the homeobox protein Prox1 (Vascular development cluster), the chemokine receptor 7 ( CxCr7 , Disulfide bond cluster), matrix metalloproteinase 13 ( Mmp13 , Embryonic morphogenesis cluster) and its transcriptional regulators Runx2 and nuclear receptor subfamily 4, group A, member 2 ( Nr4a2 ). These genes expressed at higher levels in cPLA 2 α +/+ RPM promote angiogenesis, tumor growth and invasion, and are regulated by prostaglandins and cAMP [59–66]. …”

“…Several of the genes that are differentially expressed in cPLA 2 α +/+ RPM and cPLA 2 α -/- RPM (i.e. Gdf15 , Eph2 , Ereg , Areg , Lepr , Nr4a2 , Runx2 , Mmp13 , CxCr7 , Pdpn , Prox1 ) are positively or negatively regulated in cancers compared to normal tissue as a result of prostaglandins [59–63,113]. Therefore, eicosanoids have complex biological effects depending on the tissue context, the specific receptors expressed on cells in the local environment and the timing of their production contributing to both anti- and pro-inflammation responses.…”

Phosphotyrosine profiling identifies ephrin receptor A2 as a potential therapeutic target in esophageal squamous‐cell carcinoma

“…B). Notable effectors associated with EPHA2 signaling included SRC , Src homology 2 domain containing transforming protein 1 (SHC1) , mitogen‐activated protein kinase 1 (MAPK1) , mitogen‐activated protein kinase 3 (MAPK3), cyclin‐dependent kinase 5 (CDK5) , and paxillin (PXN) .…”