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The Gab/Par pathway in development and cancer

Benjamin Neel

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Canadian Institutes of Health Research (CIHR)
Cell polarity, the generation of cellular asymmetry, is essential for numerous normal biological processes. The beautiful organization and shape of tissues, the ability of cells to migrate in specific directions, and the maintenance of stem cells all require that cell polarity be regulated properly. For these reasons, precise control of cell polarity is critical for normal development, and disordered polarity contributes to many human diseases, including cancer. A group of proteins, termed "PAR proteins" are key regulators of normal cell polarity. Until recently, it has been unclear how PAR protein functions are regulated by extracellular signals. We recently discovered that another family of proteins, the GAB proteins, act as critical intermediates between growth factor signals and polarity machinery. Specifically, we found that GAB proteins interact directly with two PAR family members, PAR1 and PAR3, and regulate their function. These interactions are critical for allowing cells to form close contacts, and also for these contacts to dissipate and enable cell movement in response to appropriate signals. Interestingly, another GAB family member, GAB2, is over-expressed in, and helps to cause, several cancers, most notably breast and ovarian tumors. We propose to further examine how the GAB and PAR proteins interact, to investigate the physiological functions of these interactions in mice, and to determine whether GAB-PAR complex interactions contribute to the cancer-promoting actions of GAB2.

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