Proteolysis of EphA2 Converts It from a Tumor Suppressor to an Oncoprotein

Abstract

Eph receptor tyrosine kinases are considered candidate therapeutic targets in cancer, but they can exert opposing effects on cell growth. In presence of its ligands, Eph receptor EphA2 suppresses signaling by other growth factor receptors, including ErbB, whereas ligand-independent activation of EphA2 augments ErbB signaling. To deploy EphA2-targeting drugs effectively in tumors, the anti-oncogenic ligand-dependent activation state of EphA2 must be discriminated from its oncogenic ligand-independent state. Since the molecular basis for the latter is little understood, we investigated how the activation state of EphA2 can be switched in tumor tissue. We found that ligand-binding domain of EphA2 is cleaved frequently by the membrane metalloproteinase MT1-MMP, a powerful modulator of the pericellular environment in tumor cells. EphA2 immunostaining revealed a significant loss of the N-terminal portion of EphA2 in areas of tumor tissue that expressed MT1-MMP. Moreover, EphA2 phosphorylation patterns that signify ligand-independent activation were observed specifically in these areas of tumor tissue. Mechanistic experiments revealed that processing of EphA2 by MT1-MMP promoted ErbB signaling, anchorage-independent growth, and cell migration. Conversely, expression of a proteolysis-resistant mutant of EphA2 prevented tumorigenesis and metastasis of human tumor xenografts in mice. Overall, our results showed how the proteolytic state of EphA2 in tumors determines its effector function and influences its status as a candidate biomarker for targeted therapy.

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

“…Overexpressed EPHA2 can be phosphorylated at S897 by activated AKT and can function in a ligand-independent manner to promote cell growth, xenograft tumor development, anoikos resistance (42), and migration of tumor cells (43)(44)(45)(46). Additionally, overexpressed EPHA2 is cleaved at the membrane by MT1-MMP metalloprotease and switches its function from ligand-dependent tumor suppressor to ligand-independent tumorpromoting factor (47,48).…”

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

“…47,48) Although Sugiyama et al 47) showed that the cleavage site was Y 385 -I and T 395 -I and Koshikawa et al 48) found that it was S-427 F and S-432 V, cleaved EphA2 had a ligand-insensitive form to promote cancer migration. Therefore, EphA2 cooperates with MT1-MMP to play a role as a tumor initiator.…”

“…In addition, cleaved EphA2 processed by MT1-MMP also activates the Ras-ERK and PI3K-Akt pathways, even when ephrin-A1 is overexpressed. 47,48) Notably, Koshikawa et al, reported that phosphoSer-897 EphA2 and MT1-MMP were co-localized in ovarian carcinoma, but not in the normal ovary. 48) In addition, cleaved EphA2 was required for tumor growth and metastasis of A431 cells in vivo.…”

“…47,48) Notably, Koshikawa et al, reported that phosphoSer-897 EphA2 and MT1-MMP were co-localized in ovarian carcinoma, but not in the normal ovary. 48) In addition, cleaved EphA2 was required for tumor growth and metastasis of A431 cells in vivo. 48) Moreover, in human invasive cutaneous squamous cell carcinoma tissue, EphA2 was also reported to be processed by MT1-MMP, and cleaved EphA2 was positively related to lymph node metastasis.…”

The Value of HER2 neu and EphA2 expressions in Gastric Adenocarcinoma Prognosis

“…It has been reported that membrane type-1 matrix metalloproteinase (MT1-MMP) on tumor cells cleaves EPHA2 at the extracellular domain and the resultant truncated and membrane-anchoring forms of EPHA2 promote oncogenic signaling [33]. These findings suggest that tumor cells contain truncated forms of EPHA2 on their cell surface which are important for EPHA2-targeting cancer therapy using monoclonal antibodies (mAbs) that mediate antibody-dependent cellular cytotoxicity (ADCC) [25].…”