p120-catenin (p120) was originally identified as a tyrosine phosphorylated substrate of oncogenic Src and of several prominent Growth Factor (GF)-activated Receptor Tyrosine Kinases (RTKs)(e.g., PDGFR, EGFR, CSF-1R). Over the past decade, p120 has emerged as a master regulator of classical cadherin stability and thus a critical determinant of cell-cell adhesion in most tissues. We have used oncogenic drivers of several downstream RTK signaling pathways to examine the role of p120 in AIG, a phenomenon typically associated with corruption of integrin signaling. Surprisingly, p120 knockdown completely blocks Src- and Rac1- (but not Ras) mediated AIG. The effect is reversed by ROCK inhibitors, consistent with our previous model, and rescuable by p120 isoform-1, but not isoform-3. Thus, we add AIG to the rapidly expanding list of cancer relevant phenotypes that are selectively dependent on isoform-1. However, the mechanism also requires E-cadherin and/or N- cadherin, depending on the oncogenic driver, a result that does not conform to prevailing notions of how AIG occurs. Similar results with respect to tumorigenesis in our APCmin:p120fl/fl mouse model of colon cancer and other observations (see background/significance) demonstrate in vivo relevance, an unappreciated bottleneck in tumor progression, and an alternative interpretation of an extensive pathology literature on p120 expression in cancer. To better appreciate the underlying mechanisms, aims 1 and 2 examine poorly understood relationships between RTK-cadherin and oncogene signaling, and the selective role of p120 isoform-1 in this process.
Aim 3 focuses on our discovery of a novel isoform-1 specific p120 binding partner linked to a spectrum of developmental brain disorders. As a potentially unifying hypothesis, we suggest that the interaction connects diverse elements of the p120 literature with emerging roles of the centrosome and cilia in multiple genetic disorders and cancer.

Public Health Relevance

p120-catenin (p120) was originally identified as a tyrosine phosphorylated substrate of oncogenic Src (Reynolds, Roesel et al. 1989) and of several prominent Growth Factor (GF)-activated Receptor Tyrosine Kinases (RTKs)(e.g., PDGFR, EGFR, CSF-1R)(Downing and Reynolds 1991;Kanner, Reynolds et al. 1991). Over the past decade, p120 has emerged as a master regulator of classical cadherin stability and thus a critical determinant of cell-cell adhesion in most tissues. In vertebrates, the catenins (p120, a catenin, b-catenin) associate with the cytoplasmic tail of classical cadherins, forming a core cadherin complex that interacts with other factors (e.g., RTKs and cytoskeletal elements) to functionally integrate cell-cell adhesion with other cellular activities required to coordinate tisue growth and morphogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM102524-01A1
Application #
8579736
Study Section
Intercellular Interactions (ICI)
Program Officer
Nie, Zhongzhen
Project Start
2013-09-01
Project End
2017-04-30
Budget Start
2013-09-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$296,145
Indirect Cost
$106,145
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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