Adhesion-Linked Protein Tyrosine Phosphatases, Morphogenesis and Breast Cancer Progression

摘要

Stromal-epithelial interactions regulate breast cell fate via integrin-growth factor receptor (GFR) interactions that activate tyrosine kinases that are tempered by protein tyrosine phosphatases (PTP). Using a series of molecular screening approaches we profiled PTP expression in normal transformed and phenotypically-reverted breast tissue and identified the Band 4.1 PTPs MEGI and D1 as candidate PTP metastasis suppressors. Our studies have implicated two Band 4.1 PTPs MEGI and D1 as important regulators of adhesion- dependent mammary morphogenesis that are consistently altered in tumors by aberrant tumor-generated mechanical force. Specifically we implicated PTP MEGI as a key regulator of adherens junction assembly/integrity and found that matrix force and tumor-generated contractility chronically increase PTP expression. Importantly ectopic elevated expression of MEGI in nonmalignant MECs enhanced their integrin-dependent cell adhesion disrupted tissue polarity and altered cell growth and survival. Studies are in progress to identify MEGI- specific effector proteins in normal transformed and phenotypically-reverted MECs and to dissect out the mechanism whereby force regulates PTP expression.