A hallmark of epithelial cancer progression is the epithelia to mesenchymal transition (EMT). In EMT the cell-cell adhesion receptor E-cadherin is lost from the plasma membrane and degraded in the lysosome and its expression is down regulated. This event results in the targeting of ?-catenin to the nucleus where it activates the transcription of genes that stimulate proliferation. The resulting mesenchymal cells are migratory and have the potential to migrate into the vasculature and lymph, initiating metastasis. We have discovered a phosphoinositide signaling pathway that regulates E-cadherin trafficking, degradation and assembly into adherens junctions in epithelial cells. The same pathway stimulates the activity of ?-catenin transcription. Phosphoinositide signaling pathways generate second messengers that target a plethora of effectors. We study the spatial and temporal generation of PI4,5P2 that controls most biological function. PI4,5P2 is synthesized by the phosphatidylinositol phosphate kinases (PIPK). Our evidence supports a key role for the PIPKI? in regulation of epithelial cell-cell contacts by an ordered set of interactions between PIPKI?, E- cadherin, ?-catenin, and trafficking components. Growth factor signaling and the tyrosine kinase Src regulate these interactions. Hypothesis and significance: PIPKI? controls the formation, stabilization and dissolution of cadherin based adherens junctions. In addition, PIPKI? associates with and stimulates ?-catenin's translocation to the nucleus and transcriptional activity. All of these events are regulated by the generation of PI4,5P2 and its regulation of effectors. These functions place PIPKI? at the center of EMT associated with cancer progression. These functions are regulated by a set of posttranslational events that drive either normal epithelial morphogenesis, or EMT, that results in increased migration and invasion. The following focused aims will assess this hypothesis (1) We will investigate the role of PIPKI? in the endocytosis of cadherins. The focus will be on the basal and growth factor stimulated E-cadherin endocytosis regulated by PIPKI?. The role of posttranslation modifications of E-cadherin and PIPKI? will be defined. (2) Delineate the role of PIPKI? isoforms in the lysosomal destruction of EGFR and E-cadherin. A newly discovered PIPKI? splice isoform sorts E-cadherin for degradation in the lysosome. The mechanism and factors involved will be defined with an emphasis on signaling pathways that control EMT. (3) PIPKI? regulation of ?-catenin transcriptional activity will be revealed. The activation of ?-catenin by PIPKI? will be integrated into pathways that are known to activate ?-catenin upon EMT.

Public Health Relevance

Cancers of epithelial origin represent at least 80% of all human cancers and are often the most difficult to cure. The life threatening aspect of epithelial cancer is metastasis and this process is dependent upon the loss of epithelial cell organization a process that is controlled by the E-cadherin receptor. E-cadherin holds epithelial cells together and suppresses growth and metastasis. When E-cadherin is lost epithelial cancers are free to metastasize or migrate to different organs. We have discovered a signaling pathway that regulates both E-cadherin's ability to hold cells together and also the loss of E-cadherin from epithelial cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Woodhouse, Elizabeth
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University of Wisconsin Madison
Schools of Medicine
United States
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Schill, Nicholas J; Hedman, Andrew C; Choi, Suyong et al. (2014) Isoform 5 of PIPKI? regulates the endosomal trafficking and degradation of E-cadherin. J Cell Sci 127:2189-203
Li, W; Anderson, R A (2014) Star-PAP controls HPV E6 regulation of p53 and sensitizes cells to VP-16. Oncogene 33:928-32
Sun, Yue; Thapa, Narendra; Hedman, Andrew C et al. (2013) Phosphatidylinositol 4,5-bisphosphate: targeted production and signaling. Bioessays 35:513-22
Sun, Yue; Hedman, Andrew C; Tan, Xiaojun et al. (2013) Endosomal type I? PIP 5-kinase controls EGF receptor lysosomal sorting. Dev Cell 25:144-55
Thapa, Narendra; Sun, Yue; Schramp, Mark et al. (2012) Phosphoinositide signaling regulates the exocyst complex and polarized integrin trafficking in directionally migrating cells. Dev Cell 22:116-30
Schramp, Mark; Thapa, Narendra; Heck, Jessica et al. (2011) PIPKI? regulates ?-catenin transcriptional activity downstream of growth factor receptor signaling. Cancer Res 71:1282-91
Sun, Yue; Turbin, Dmitry A; Ling, Kun et al. (2010) Type I gamma phosphatidylinositol phosphate kinase modulates invasion and proliferation and its expression correlates with poor prognosis in breast cancer. Breast Cancer Res 12:R6
Thieman, James R; Mishra, Sanjay K; Ling, Kun et al. (2009) Clathrin regulates the association of PIPKIgamma661 with the AP-2 adaptor beta2 appendage. J Biol Chem 284:13924-39
Schill, Nicholas J; Anderson, Richard A (2009) Out, in and back again: PtdIns(4,5)P(2) regulates cadherin trafficking in epithelial morphogenesis. Biochem J 418:247-60
Schill, Nicholas J; Anderson, Richard A (2009) Two novel phosphatidylinositol-4-phosphate 5-kinase type Igamma splice variants expressed in human cells display distinctive cellular targeting. Biochem J 422:473-82

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