Investigators' Information

Detail Information for Assoc Professor Albert B. Reynolds

Assoc Professor Albert B. Reynolds

Degree: Ph. D.
Affiliation: Assoc. Professor of Cell Biology

Department: Cell Biology

Room#: B-2104B MCN

Phone#: 343-9532

Fax#:

E-Mail: Al Reynolds/VUMC/Vanderbilt@vanderbilt.edu

Research Description:     One of the hallmarks of malignant cells is the ability to overcome cell-cell adhesion and invade surrounding tissues. Expression of the main adhesion molecule in epithelia, E-cadherin, is frequently lost in tumors from patients with epithelial cancers implying an involvement in carcinogenesis. The effect is likely to be direct because re-establishing E-cadherin function in tumor cell lines can reverse the invasive phenotype. Moreover, experiments in transgenic mice strongly suggest that loss of E-cadherin directly promotes the transition of a benign adenoma into a carcinoma. While most evidence suggests that E-cadherin loss is a late event in tumorigenesis, in lobular carcinoma of the breast, and in gastric carcinoma, the E-cadherin gene is often directly mutated and its loss of function may be an early, if not causal event. Accumulating evidence indicates that defects in the cytoplasmic mediators of cadherin function, the catenins, may account for cadherin dysfunction in carcinomas where E-cadherin expression is apparently normal. My laboratory identified a new catenin, termed p120ctn (hereafter p120), and discovered that it binds directly to the cytoplasmic domain of cell to cell adhesion receptor, E-cadherin. Originally characterized as a prominent substrate for Src and receptor protein tyrosine kinases (eg, the EGF receptor) it now appears that p120’s major role in cells is to regulate cadherin-mediated cell-cell adhesion. Interestingly, recent immunohistochemical studies indicate that p120 expression is altered in ~10% of ductal carcinomas of the breast and ~18% of colon cancers. p120 loss of function would be predicted to have severe consequences on cadherin mediated cell-cell adhesion, perhaps mimicking the invasive behavior of cells lacking E-cadherin. Whereas the classical catenins (a-, b-, and g-catenins) have been studied extensively, the importance of p120 in cadherin function has only recently been appreciated and less is known about its potential role in cancer. The laboratory is pursuing several major lines of research. For example, we are utilizing a unique model system to uncouple p120 and E-cadherin function to determine the role of mutant E-cadherin proteins that are selectively deficient in binding p120. In addition, we are using genetic and molecular approaches to directly address the role of p120 by structure-function analysis. In another approach, we are mapping the sites of Src and PTK receptor induced tyrosine phosphorylation with the long range goal of determining the role of p120 in signaling and transformation. Finally, we have identified a novel interaction between p120 and a transcription factor, termed Kaiso, that suggests a nuclear signaling pathway involving p120. Cell-cell adhesion, PTK signaling and tumor invasiveness are interconnected processes; an intriguing possibility, supported by the well established functions of b-catenin in cancer, is that p120 - cadherin interactions may play a role in the contact inhibition of cell growth, a hallmark of malignancy which has yet to be explained at the molecular level.

Publications: Peifer M, Berg S, Reynolds AB. A repeating amino acid motif shared by proteins with diverse cellular roles. Cell 76:789-791, 1994.

Reynolds AB, Daniel J, McCrea P, Wheelock MJ, Wu J, Zhang Z. Identification of a new catenin: the tyrosine kinase substrate p120cas associates with E-cadherin complexes. Mol Cell Biol, 14:8333-8342, 1994.

Daniel J, Reynolds AB. The tyrosine kinase substrate p120cas binds directly to E-Cadherin but not to the adenomatous polyposis coli protein or a-Catenin. Mol Cell Biol. 15:4819-4824, 1995.

Reynolds AB, Jenkins NA, Gilbert DJ, Copeland NG, Shapiro DN, Wu J, Daniel JM, Mo Y-Y. The gene encoding p120cas, a novel catenin, is located on human chromosome 11q11 (CTNNS) and mouse chromosome 2(Catns). Genomics, 31:127-129, 1996.

Daniel JM, Reynolds AB. Tyrosine phosphorylation and cadherin / catenin function. BioEssays, 19:883-991, 1997.

Wu J, Mariner D, Thoreson M, Reynolds AB. Production and characterization of monoclonal antibodies to the catenin p120ctn. Hybridoma, 17:175-183, 1998.

Updated Date: 8/26/99

Research Description:	One of the hallmarks of malignant cells is the ability to overcome cell-cell adhesion and invade surrounding tissues. Expression of the main adhesion molecule in epithelia, E-cadherin, is frequently lost in tumors from patients with epithelial cancers implying an involvement in carcinogenesis. The effect is likely to be direct because re-establishing E-cadherin function in tumor cell lines can reverse the invasive phenotype. Moreover, experiments in transgenic mice strongly suggest that loss of E-cadherin directly promotes the transition of a benign adenoma into a carcinoma. While most evidence suggests that E-cadherin loss is a late event in tumorigenesis, in lobular carcinoma of the breast, and in gastric carcinoma, the E-cadherin gene is often directly mutated and its loss of function may be an early, if not causal event. Accumulating evidence indicates that defects in the cytoplasmic mediators of cadherin function, the catenins, may account for cadherin dysfunction in carcinomas where E-cadherin expression is apparently normal. My laboratory identified a new catenin, termed p120ctn (hereafter p120), and discovered that it binds directly to the cytoplasmic domain of cell to cell adhesion receptor, E-cadherin. Originally characterized as a prominent substrate for Src and receptor protein tyrosine kinases (eg, the EGF receptor) it now appears that p120’s major role in cells is to regulate cadherin-mediated cell-cell adhesion. Interestingly, recent immunohistochemical studies indicate that p120 expression is altered in ~10% of ductal carcinomas of the breast and ~18% of colon cancers. p120 loss of function would be predicted to have severe consequences on cadherin mediated cell-cell adhesion, perhaps mimicking the invasive behavior of cells lacking E-cadherin. Whereas the classical catenins (a-, b-, and g-catenins) have been studied extensively, the importance of p120 in cadherin function has only recently been appreciated and less is known about its potential role in cancer. The laboratory is pursuing several major lines of research. For example, we are utilizing a unique model system to uncouple p120 and E-cadherin function to determine the role of mutant E-cadherin proteins that are selectively deficient in binding p120. In addition, we are using genetic and molecular approaches to directly address the role of p120 by structure-function analysis. In another approach, we are mapping the sites of Src and PTK receptor induced tyrosine phosphorylation with the long range goal of determining the role of p120 in signaling and transformation. Finally, we have identified a novel interaction between p120 and a transcription factor, termed Kaiso, that suggests a nuclear signaling pathway involving p120. Cell-cell adhesion, PTK signaling and tumor invasiveness are interconnected processes; an intriguing possibility, supported by the well established functions of b-catenin in cancer, is that p120 - cadherin interactions may play a role in the contact inhibition of cell growth, a hallmark of malignancy which has yet to be explained at the molecular level.

Publications:	Peifer M, Berg S, Reynolds AB. A repeating amino acid motif shared by proteins with diverse cellular roles. Cell 76:789-791, 1994.
	Reynolds AB, Daniel J, McCrea P, Wheelock MJ, Wu J, Zhang Z. Identification of a new catenin: the tyrosine kinase substrate p120cas associates with E-cadherin complexes. Mol Cell Biol, 14:8333-8342, 1994.
	Daniel J, Reynolds AB. The tyrosine kinase substrate p120cas binds directly to E-Cadherin but not to the adenomatous polyposis coli protein or a-Catenin. Mol Cell Biol. 15:4819-4824, 1995.
	Reynolds AB, Jenkins NA, Gilbert DJ, Copeland NG, Shapiro DN, Wu J, Daniel JM, Mo Y-Y. The gene encoding p120cas, a novel catenin, is located on human chromosome 11q11 (CTNNS) and mouse chromosome 2(Catns). Genomics, 31:127-129, 1996.
	Daniel JM, Reynolds AB. Tyrosine phosphorylation and cadherin / catenin function. BioEssays, 19:883-991, 1997.
	Wu J, Mariner D, Thoreson M, Reynolds AB. Production and characterization of monoclonal antibodies to the catenin p120ctn. Hybridoma, 17:175-183, 1998.