The role of the low molecular weight protein tyrosine phosphatase (LMW-PTP) and the EphA2 kinase in human mammary cancer

Keith D Kikawa, Purdue University

Abstract

It is generally understood that intracellular signaling by protein tyrosine phosphorylation governs many aspects of cellular behavior. The biological consequences of this signaling pathway are important because the levels of protein tyrosine phosphorylation are frequently elevated in cancer cells. In the classic paradigm, tyrosine kinases promote tumor cell growth, survival and invasiveness whereas tyrosine phosphatases negatively regulate these same behaviors. However, in the case of one particular tyrosine phosphatase, LMW-PTP, this is not so. This thesis demonstrates that LMW-PTP is frequently overexpressed in transformed breast epithelial cells and the overexpression of LMW-PTP is sufficient to confer transformation upon non-transformed epithelial cells. The EphA2 receptor tyrosine kinase is shown to be a prominent substrate for LMW-PTP and the oncogenic activities of LMW-PTP are linked to altered EphA2 expression and function. This is significant because EphA2 is overexpressed and functionally altered in a variety of cancers. Additionally, the effects of inhibiting LMW-PTP activity in malignant breast epithelial cells are examined. When overexpressed in a malignantly transformed epithelial cell line, the D129A catalytically inactive mutation of LMW-PTP is shown to reduce the ability of these cells to grow and survive in three-dimensional assays, indicating a reduction of the transformed phenotype. Moreover, inhibiting LMW-PTP activity results in EphA2 expression and function resembling that found in non-transformed cells and negate the responsiveness of these cells to EphA2 inhibitors. These results suggest that LMW-PTP is a promising target in cancer and link its oncogenic behaviors to EphA2.

Degree

Ph.D.

Advisors

Hannon, Purdue University.

Subject Area

Cellular biology|Biochemistry

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