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.
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.
|Yu, Huapeng H; Dohn, Michael R; Markham, Nicholas O et al. (2016) p120-catenin controls contractility along the vertical axis of epithelial lateral membranes. J Cell Sci 129:80-94|
|Hendley, Audrey M; Wang, Yue J; Polireddy, Kishore et al. (2016) p120 Catenin Suppresses Basal Epithelial Cell Extrusion in Invasive Pancreatic Neoplasia. Cancer Res 76:3351-63|
|Yang, Zhiyong; Sun, Dong; Yan, Zhibo et al. (2014) Differential role for p120-catenin in regulation of TLR4 signaling in macrophages. J Immunol 193:1931-41|
|Lang, Richard A; Herman, Ken; Reynolds, Albert B et al. (2014) p120-catenin-dependent junctional recruitment of Shroom3 is required for apical constriction during lens pit morphogenesis. Development 141:3177-87|
|Reynolds, A B; Kanner, S B; Bouton, A H et al. (2014) SRChing for the substrates of Src. Oncogene 33:4537-47|
|Koh, Dong-In; Han, Dohyun; Ryu, Hoon et al. (2014) KAISO, a critical regulator of p53-mediated transcription of CDKN1A and apoptotic genes. Proc Natl Acad Sci U S A 111:15078-83|
|Markham, Nicholas O; Doll, Caleb A; Dohn, Michael R et al. (2014) DIPA-family coiled-coils bind conserved isoform-specific head domain of p120-catenin family: potential roles in hydrocephalus and heterotopia. Mol Biol Cell 25:2592-603|
|Wang, Yan-Lei; Malik, Asrar B; Sun, Yu et al. (2011) Innate immune function of the adherens junction protein p120-catenin in endothelial response to endotoxin. J Immunol 186:3180-3187|