Profile

My laboratory combines molecular and biochemical approaches with 3D culture and mouse models of colon and breast cancer to study the roles of p120-catenin (p120) in cell-cell adhesion, tumorigenesis and metastasis. Most proteins linked physically or functionally to p120 are, in fact, tumor suppressors or oncogenes (eg, Src, Receptor Tyrosine kinases, Rho GTPases, E-cadherin, B-catenin, Adenomatous Polyposis Coli), implying a role for p120 in cancer. Previously, we showed that p120 interaction is essential for cadherin stability at the cell surface. For example, p120 knockdown in many epithelial cell lines (eg, MCF10A, A431) causes rapid degradation of the entire E-cadherin complex and partial or complete loss of cell-cell adhesion. These observations have led to the notion that p120 itself is a tumor and/or metastasis suppressor - on its own, or in collaboration with E-cadherin. Indeed, E-cadherin is broadly established as a tumor and metastasis suppressor and p120 is frequently downregulated and/or mislocalized in most major human cancers (e.g. colon, breast, lung, pancreas, prostate).

We are heavily invested in mouse models of colon cancer. Using conditional p120 KO in APC mutant mice, we recently found that p120 is, in fact, a haploinsufficient tumor suppressor in the colon (and probably other tissues). Interestingly, loss of one p120 allele increases tumor number by 10 fold. Although biallic loss is well tolerated in wild type intestinal epithelium, it is not permitted in the context of the tumor. Based on data from Sleeping Beauty insertional mutagenesis screens (in collaboration with Neal Copeland) we have extended these findings to a-catenin and E-cadherin, and to several different oncogenic backgrounds (e.g., K-Ras, Smad4, p53). Thus, it appears that loss of E-cadherin complex components is not restricted to late stage tumors. Instead, very early loss of any single allele for p120, a-catenin or E-cadherin likely comprises a major bottleneck to tumor progression, exceeded only by the mandatory initiating mutation in APC.

In the mammary gland, we are using a well-characterized MMTV-mT breast cancer model to examine the role of p120 in metastasis. Interestingly, in contrast to the intestine, the mammary gland does not form at all in the absence of p120. Transformation by mT, on the other hand, rescues the epithelium and gives rise to p120 null primary tumors. However, tumor cells lacking p120 cannot metastasize to the lung. Thus, we have arrived at a unique and powerful system for examining not only the role of p120 (and p120 isoforms) in metastasis, but also recently postulated roles for EMT and ???stemness??? as they pertain to the metastatic process. The system is complemented by mechanistic studies based on ex-vivo manipulation of cells follow by reconstitution in vivo or in in vitro 3D cell cultures.

Finally, A third line of research focuses on the transcription factor Kaiso, discovered some time ago in our lab as a direct p120 binding partner. The interaction is reminiscent of Wnt-pathway mediated B-catenin ??? TCF4 interactions and may connect p120 to the nucleus. The Kaiso landscape is evolving rapidly in the wake of whole genome sequencing technologies such as ChipSEQ. We are examining different aspects of Kaiso activity in intestinal and mammary systems and moving into exciting new areas including epigenetics, transcription and genome maintenance. Kaiso is going to be an exciting place to be over the next decade.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. p120-catenin controls contractility along the vertical axis of epithelial lateral membranes. Yu HH, Dohn MR, Markham NO, Coffey RJ, Reynolds AB (2016) J Cell Sci 129(1): 80-94
    › Primary publication · 26585313 (PubMed) · PMC4732297 (PubMed Central)
  2. p120-catenin expressed in alveolar type II cells is essential for the regulation of lung innate immune response. Chignalia AZ, Vogel SM, Reynolds AB, Mehta D, Dull RO, Minshall RD, Malik AB, Liu Y (2015) Am J Pathol 185(5): 1251-63
    › Primary publication · 25773174 (PubMed) · PMC4419206 (PubMed Central)
  3. p120 Catenin is required for normal tubulogenesis but not epithelial integrity in developing mouse pancreas. Hendley AM, Provost E, Bailey JM, Wang YJ, Cleveland MH, Blake D, Bittman RW, Roeser JC, Maitra A, Reynolds AB, Leach SD (2015) Dev Biol 399(1): 41-53
    › Primary publication · 25523391 (PubMed) · PMC4868343 (PubMed Central)
  4. CD148 tyrosine phosphatase promotes cadherin cell adhesion. Takahashi K, Matafonov A, Sumarriva K, Ito H, Lauhan C, Zemel D, Tsuboi N, Chen J, Reynolds A, Takahashi T (2014) PLoS One 9(11): e112753
    › Primary publication · 25386896 (PubMed) · PMC4227875 (PubMed Central)
  5. KAISO, a critical regulator of p53-mediated transcription of CDKN1A and apoptotic genes. Koh DI, Han D, Ryu H, Choi WI, Jeon BN, Kim MK, Kim Y, Kim JY, Parry L, Clarke AR, Reynolds AB, Hur MW (2014) Proc Natl Acad Sci U S A 111(42): 15078-83
    › Primary publication · 25288747 (PubMed) · PMC4210320 (PubMed Central)
  6. p120-catenin-dependent junctional recruitment of Shroom3 is required for apical constriction during lens pit morphogenesis. Lang RA, Herman K, Reynolds AB, Hildebrand JD, Plageman TF (2014) Development 141(16): 3177-87
    › Primary publication · 25038041 (PubMed) · PMC4197547 (PubMed Central)
  7. Differential role for p120-catenin in regulation of TLR4 signaling in macrophages. Yang Z, Sun D, Yan Z, Reynolds AB, Christman JW, Minshall RD, Malik AB, Zhang Y, Hu G (2014) J Immunol 193(4): 1931-41
    › Primary publication · 25015829 (PubMed) · PMC4119481 (PubMed Central)
  8. DIPA-family coiled-coils bind conserved isoform-specific head domain of p120-catenin family: potential roles in hydrocephalus and heterotopia. Markham NO, Doll CA, Dohn MR, Miller RK, Yu H, Coffey RJ, McCrea PD, Gamse JT, Reynolds AB (2014) Mol Biol Cell 25(17): 2592-603
    › Primary publication · 25009281 (PubMed) · PMC4148249 (PubMed Central)
  9. N-cadherin regulates spatially polarized signals through distinct p120ctn and β-catenin-dependent signalling pathways. Ouyang M, Lu S, Kim T, Chen CE, Seong J, Leckband DE, Wang F, Reynolds AB, Schwartz MA, Wang Y (2013) Nat Commun : 1589
    › Primary publication · 23481397 (PubMed) · PMC3602931 (PubMed Central)
  10. A membrane fusion protein αSNAP is a novel regulator of epithelial apical junctions. Naydenov NG, Brown B, Harris G, Dohn MR, Morales VM, Baranwal S, Reynolds AB, Ivanov AI (2012) PLoS One 7(4): e34320
    › Primary publication · 22485163 (PubMed) · PMC3317505 (PubMed Central)
  11. p120-catenin is essential for terminal end bud function and mammary morphogenesis. Kurley SJ, Bierie B, Carnahan RH, Lobdell NA, Davis MA, Hofmann I, Moses HL, Muller WJ, Reynolds AB (2012) Development 139(10): 1754-64
    › Primary publication · 22461563 (PubMed) · PMC3328177 (PubMed Central)
  12. Regulation of cochlear convergent extension by the vertebrate planar cell polarity pathway is dependent on p120-catenin. Chacon-Heszele MF, Ren D, Reynolds AB, Chi F, Chen P (2012) Development 139(5): 968-78
    › Primary publication · 22318628 (PubMed) · PMC3274358 (PubMed Central)
  13. The evolutionary history of the catenin gene family during metazoan evolution. Zhao ZM, Reynolds AB, Gaucher EA (2011) BMC Evol Biol : 198
    › Primary publication · 21740572 (PubMed) · PMC3141441 (PubMed Central)
  14. Epithelial organization: new perspective on α-catenin from an ancient source. Reynolds AB (2011) Curr Biol 21(11): R430-2
    › Primary publication · 21640901 (PubMed)
  15. Deletion of p120-catenin results in a tumor microenvironment with inflammation and cancer that establishes it as a tumor suppressor gene. Stairs DB, Bayne LJ, Rhoades B, Vega ME, Waldron TJ, Kalabis J, Klein-Szanto A, Lee JS, Katz JP, Diehl JA, Reynolds AB, Vonderheide RH, Rustgi AK (2011) Cancer Cell 19(4): 470-83
    › Primary publication · 21481789 (PubMed) · PMC3077713 (PubMed Central)
  16. Alterations in the proteome of the NHERF2 knockout mouse jejunal brush border membrane vesicles. Donowitz M, Singh S, Singh P, Chakraborty M, Chen Y, Murtazina R, Gucek M, Cole RN, Zachos NC, Salahuddin FF, Kovbasnjuk O, Broere N, Smalley-Freed WG, Reynolds AB, Hubbard AL, Seidler U, Weinman E, de Jonge HR, Hogema BM, Li X (2011) Physiol Genomics 43(11): 674-84
    › Primary publication · 21427361 (PubMed) · PMC3121161 (PubMed Central)
  17. Innate immune function of the adherens junction protein p120-catenin in endothelial response to endotoxin. Wang YL, Malik AB, Sun Y, Hu S, Reynolds AB, Minshall RD, Hu G (2011) J Immunol 186(5): 3180-3187
    › Primary publication · 21278343 (PubMed) · PMC4277845 (PubMed Central)
  18. Xenopus Kazrin interacts with ARVCF-catenin, spectrin and p190B RhoGAP, and modulates RhoA activity and epithelial integrity. Cho K, Vaught TG, Ji H, Gu D, Papasakelariou-Yared C, Horstmann N, Jennings JM, Lee M, Sevilla LM, Kloc M, Reynolds AB, Watt FM, Brennan RG, Kowalczyk AP, McCrea PD (2010) J Cell Sci 123(Pt 23): 4128-44
    › Primary publication · 21062899 (PubMed) · PMC2987443 (PubMed Central)
  19. Integrated biochemical and mechanical signals regulate multifaceted human embryonic stem cell functions. Li D, Zhou J, Wang L, Shin ME, Su P, Lei X, Kuang H, Guo W, Yang H, Cheng L, Tanaka TS, Leckband DE, Reynolds AB, Duan E, Wang F (2010) J Cell Biol 191(3): 631-44
    › Primary publication · 20974810 (PubMed) · PMC3003326 (PubMed Central)
  20. p120 regulates endothelial permeability independently of its NH2 terminus and Rho binding. Herron CR, Lowery AM, Hollister PR, Reynolds AB, Vincent PA (2011) Am J Physiol Heart Circ Physiol 300(1): H36-48
    › Primary publication · 20971762 (PubMed) · PMC3023255 (PubMed Central)
  21. A p120-catenin-CK1epsilon complex regulates Wnt signaling. Casagolda D, Del Valle-Pérez B, Valls G, Lugilde E, Vinyoles M, Casado-Vela J, Solanas G, Batlle E, Reynolds AB, Casal JI, de Herreros AG, Duñach M (2010) J Cell Sci 123(Pt 15): 2621-31
    › Primary publication · 20940130 (PubMed)
  22. Targeted p120-catenin ablation disrupts dental enamel development. Bartlett JD, Dobeck JM, Tye CE, Perez-Moreno M, Stokes N, Reynolds AB, Fuchs E, Skobe Z (2010) PLoS One 5(9)
    › Primary publication · 20862276 (PubMed) · PMC2940824 (PubMed Central)
  23. Immunocytochemical localization and determination of hormone-induced synthesis of the sulfated oviductal glycoproteins. Oliphant G, Reynolds AB, Smith PF, Ross PR, Marta JS (1984) Biol Reprod 31(1): 165-74
    › Primary publication · 6380601 (PubMed)