Untitled

Abstract

Cancer is a disease of aberrant signal transduction. The expression and function of intracellular signaling pathways are frequently subverted as cells progress towards a metastatic phenotype. In particular, tyrosine kinases initiate powerful signals that govern many different aspects of cell behavior. In Recent studies have demonstrated that the EphA2 receptor tyrosine kinase is frequently overexpressed and functionally altered in aggressive tumor cells, and that these changes promote metastatic character. Herein, we provide an overview of our current understanding of EphA2, with emphasis upon the differential regulation of EphA2 expression and function. We also show that differential EphA2 expression and function may provide a unique opportunity for selective therapeutic targeting of EphA2 in metastatic disease.

RETRACTED ARTICLE: EphA2: a determinant of malignant cellular behavior and a potential therapeutic target in pancreatic adenocarcinoma

“…Conversely, in malignant disease, which is characterized by abnormal tissue organization, EphA2 overexpression is common and normal ephrin A1 binding is reduced (Bartley et al, 1994;Zantek et al, 1999). EphA2 is usually degraded following ligand binding (Carles- Walker-Daniels et al, 2002) but, when EphA2 is overexpressed, impaired ligand binding is thought to stabilize EphA2, leading to a further impairment of ligand binding and EphA2 accumulation (Kinch and Carles-Kinch, 2003). In the presence of EphA2 overexpression, suppression of tumor growth, decreased cellular invasiveness and inhibition of Ras/ MAPK cascade activity, all of which are normally induced by ephrin A1 binding, no longer occur (Miao et al, 2001;Zelinski et al, 2001).…”

“…These interactions are postulated to prevent aberrant cellular migration across embryonic boundaries, thus maintaining normal tissue organization. In malignancy, characterized by deranged tissue organization, differential expression and functional alterations of Eph kinases have been reported to be prevalent (Kinch and Carles-Kinch, 2003;WalkerDaniels et al, 2003).…”

AURKA is one of the downstream targets of MAPK1/ERK2 in pancreatic cancer

“…They included genes encoding cyclins such as CCNA2, CCNB1, CCNB2 and CCNE2 (Hunter and Pines, 1991), kinetocore-related molecules such as AURKA, AURKB, CENPA and CENPF (Hussein and Taylor, 2002;Kunitoku et al, 2003;Marumoto et al, 2005), microtubule-associated molecules such as TPX2 and KIF2C (Kufer et al, 2002;Hunter et al, 2003), RRM1 encoding ribonucleotide reductase (Parker et al, 1995), POLQ encoding DNA polymerase theta (Sharief et al, 1999), PRIM1 encoding DNA primase (Stadlbauer et al, 1994), MCM4 encoding DNA replication-initiation factor (Musahl et al, 1995) and RFC4 encoding DNA replication factor (Wang et al, 2000). Genes of interest in terms of implication in cancer progression were MMP1 and EPHA2; both are associated with invasion and metastasis (Kinch and Carles-Kinch, 2003;Seiki and Yana, 2003). ETS1 is also interesting because it encodes a transcription factor mediating transcription of some cancer-related genes and is known to be one of the downstream target genes of MAPK1 (Foulds et al, 2004).…”

Adenoviral Vectors: Potential and Challenges as a Gene Delivery System

“…Ecadherin, a cell adhesion molecule, is also able to phosphorylate EphA2 and aid in proper localization of the receptor. In many cancer cells, EphA2 is over expressed, unphosphorylated and unable to bind to its ligands due to its altered localization (Kinch & Carles-Kinch, 2003;Zantek et al, 1999). Monoclonal antibodies directed against EphA2 have been used in order to mimic ligand-induced downregulation.…”