{"@context":"http://iiif.io/api/presentation/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/manifest.json","@type":"sc:Manifest","label":"Functional study of classical Protein Tyrosine Phosphatases in mammary epithelial cells","metadata":[{"label":"dc.description.sponsorship","value":"This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree."},{"label":"dc.format","value":"Monograph"},{"label":"dc.format.medium","value":"Electronic Resource"},{"label":"dc.identifier.uri","value":"http://hdl.handle.net/11401/76497"},{"label":"dc.language.iso","value":"en_US"},{"label":"dc.publisher","value":"The Graduate School, Stony Brook University: Stony Brook, NY."},{"label":"dcterms.abstract","value":"Reversible protein tyrosine phosphorylation is critical for the dynamic regulation of protein function and is maintained by the synchronized and complementary activity of Protein Tyrosine Kinases (PTKs) and Protein Tyrosine Phosphatases (PTPs). Although considerable progress has been made in understanding the function of PTKs, the study of PTPs has lagged behind. Some PTPs have been implicated as products of oncogenes or tumor suppressors. Particularly in breast cancers driven by the oncogenic receptor tyrosine kinase ERBB2, there is evidence for PTPs playing diverse regulatory roles, suggesting that systematic analysis of PTP function could yield important insights into this field which could, in turn, aid the search for novel therapeutic strategies against ERBB2-positive breast cancers. The goal of this thesis project was to investigate the role of classical PTPs in mammary epithelial cell function using organotypic culture as a model system. I carried out an RNAi-based screen to investigate the effects of loss of PTPs in the context of ERBB2 signaling, on morphogenesis in three-dimensional matrigel, using architecture as readout for tumorigenic potential. I found nine candidate PTPs, suppression of which had distinct outcomes with respect to acinus architecture. This included both positive and negative regulators of ERBB2 signaling, thereby highlighting the specificity of PTPs in this signal transduction pathway. The study revealed a novel role for PTPD2 as a positive regulator of the ERBB2 signaling pathway. Suppression of PTPD2 attenuated the multiacinar phenotype of activated ERBB2 in three-dimensional cultures, specifically by inhibiting ERBB2-mediated loss of polarity and lumen filling. In contrast, overexpression of PTPD2 enhanced the ERBB2 phenotype. I also found that the lipid second messenger, phosphatidic acid, bound PTPD2 in vitro and enhanced its catalytic activity. Small-molecule inhibitors against Phospholipase D (PLD), an enzyme that produces phosphatidic acid in cells, also attenuated the ERBB2 phenotype. Exogenously added phosphatidic acid was able to rescue the PLD-inhibition phenotype, but only when PTPD2 was present. These findings point towards a novel pathway involving the Protein Tyrosine Phosphatase PTPD2 and the lipid second messenger phosphatidic acid, that acts positively to regulate ERBB2 signaling and may, in the future, be a source of therapeutic targets."},{"label":"dcterms.available","value":"2017-09-20T16:50:26Z"},{"label":"dcterms.contributor","value":"Muthuswamy, Senthil."},{"label":"dcterms.creator","value":"Ramesh, Mathangi"},{"label":"dcterms.dateAccepted","value":"2017-09-20T16:50:26Z"},{"label":"dcterms.dateSubmitted","value":"2017-09-20T16:50:26Z"},{"label":"dcterms.description","value":"Department of Molecular and Cellular Biology."},{"label":"dcterms.extent","value":"147 pg."},{"label":"dcterms.format","value":"Monograph"},{"label":"dcterms.identifier","value":"http://hdl.handle.net/11401/76497"},{"label":"dcterms.issued","value":"2015-12-01"},{"label":"dcterms.language","value":"en_US"},{"label":"dcterms.provenance","value":"Made available in DSpace on 2017-09-20T16:50:26Z (GMT). No. of bitstreams: 1\nRamesh_grad.sunysb_0771E_12232.pdf: 9644072 bytes, checksum: 274030f36e14ee05b27db9355c22e100 (MD5)\n  Previous issue date:    1"},{"label":"dcterms.publisher","value":"The Graduate School, Stony Brook University: Stony Brook, NY."},{"label":"dcterms.subject","value":"Molecular biology"},{"label":"dcterms.title","value":"Functional study of classical Protein Tyrosine Phosphatases in mammary epithelial cells"},{"label":"dcterms.type","value":"Dissertation"},{"label":"dc.type","value":"Dissertation"}],"description":"This manifest was generated dynamically","viewingDirection":"left-to-right","sequences":[{"@type":"sc:Sequence","canvases":[{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json","@type":"sc:Canvas","label":"Page 1","height":1650,"width":1275,"images":[{"@type":"oa:Annotation","motivation":"sc:painting","resource":{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/12%2F86%2F64%2F128664332031359086858707582905350769612/full/full/0/default.jpg","@type":"dctypes:Image","format":"image/jpeg","height":1650,"width":1275,"service":{"@context":"http://iiif.io/api/image/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/12%2F86%2F64%2F128664332031359086858707582905350769612","profile":"http://iiif.io/api/image/2/level2.json"}},"on":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json"}]}]}]}