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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104708-08
Application #
8250252
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Woodhouse, Elizabeth
Project Start
2003-12-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$288,391
Indirect Cost
$94,188
Name
University of Wisconsin Madison
Department
Pharmacology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Tan, Xiaojun; Lambert, Paul F; Rapraeger, Alan C et al. (2016) Stress-Induced EGFR Trafficking: Mechanisms, Functions, and Therapeutic Implications. Trends Cell Biol 26:352-66
Thapa, Narendra; Tan, Xiaojun; Choi, Suyong et al. (2016) The Hidden Conundrum of Phosphoinositide Signaling in Cancer. Trends Cancer 2:378-390
Choi, Suyong; Anderson, Richard A (2016) IQGAP1 is a phosphoinositide effector and kinase scaffold. Adv Biol Regul 60:29-35
Tan, Xiaojun; Thapa, Narendra; Liao, Yihan et al. (2016) PtdIns(4,5)P2 signaling regulates ATG14 and autophagy. Proc Natl Acad Sci U S A 113:10896-901
Choi, Suyong; Thapa, Narendra; Tan, Xiaojun et al. (2015) PIP kinases define PI4,5Pâ‚‚signaling specificity by association with effectors. Biochim Biophys Acta 1851:711-23
Tan, Xiaojun; Thapa, Narendra; Choi, Suyong et al. (2015) Emerging roles of PtdIns(4,5)P2--beyond the plasma membrane. J Cell Sci 128:4047-56
Thapa, Narendra; Choi, Suyong; Tan, Xiaojun et al. (2015) Phosphatidylinositol Phosphate 5-Kinase Iγ and Phosphoinositide 3-Kinase/Akt Signaling Couple to Promote Oncogenic Growth. J Biol Chem 290:18843-54
Tan, Xiaojun; Thapa, Narendra; Sun, Yue et al. (2015) A kinase-independent role for EGF receptor in autophagy initiation. Cell 160:145-60
Tan, Xiaojun; Sun, Yue; Thapa, Narendra et al. (2015) LAPTM4B is a PtdIns(4,5)P2 effector that regulates EGFR signaling, lysosomal sorting, and degradation. EMBO J 34:475-90
Schill, Nicholas J; Hedman, Andrew C; Choi, Suyong et al. (2014) Isoform 5 of PIPKIγ regulates the endosomal trafficking and degradation of E-cadherin. J Cell Sci 127:2189-203

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