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The VICC.ORG Investigator Directory

Albert B. Reynolds, Ph.D.

Professor
VICC Member
Researcher

Contact Information:

Vanderbilt University Medical Center
440-C Preston Building
Nashville, TN 37232-6840
615-343-9532

Research Specialty:

The role of the catenin p120 in signaling, cell-cell adhesion, and cancer.

Research Description:

Our main focus is to elucidate the many roles of p120-catenin (p120) in cadherin mediated cell-cell adhesion and cancer. Over 90% of human cancer derives from the epithelial linings of the major organs (eg, colon, breast, prostate, lung, pancreas). The process is initiated by mutations in oncogenes and/or tumor suppressors, which generally corrupt epithelial structure/function during tumorigenesis. Additional changes eventually lead to metastasis, the phenomenon responsible for most cancer mortality. p120 is believed to play fundamental roles in these events.

Cadherins are cell-cell adhesion receptors with critical roles in development, morphogenesis, and cancer. Epithelial cadherin (E-cadherin) is the main cell-cell adhesion protein in epithelial tissues and is regarded as a master organizer of epithelial structure and function. Importantly, transition to metastasis in many carcinoma types (eg, colon, breast, prostate, lung, pancreas) has been causally linked to E-cadherin downregulation. p120-catenin (p120) was originally described as a substrate for oncogenic Src- and Receptor-Tyrosine Kinases, and later identified as a catenin, one of several proteins that directly interact with the cadherin cytoplasmic tail. Collectively, the catenins (α-, β-, and p120-catenin) regulate cadherin function, in part, by mediating physical and/or functional interactions between cadherins and the underlying actin cytoskeleton.

Most proteins linked physically or functionally to p120 are, in fact, tumor suppressors or oncogenes (eg, Src, Receptor Tyrosine kinases, Rho GTPases, E-cadherin, β-catenin, Wnt, Adenomatous Polyposis Coli), implying a role for p120 in cancer. We have shown that p120 acts at the cell surface to regulate cadherin stability, thereby controlling the amount of cadherin available for cell-cell adhesion. p120 knockdown in many epithelial cell lines (eg, MCF10A, A431) causes degradation of the cadherin complex and loss of cell-cell adhesion. Together, these observations raise the possibility that p120 itself is a tumor and/or metastasis suppressor - on its own, or in collaboration with E-cadherin. Indeed, the pathology literature shows that p120 is frequently downregulated in human tumors but how and whether this contributes to tumorigenesis is as yet unclear.

To directly examine roles for p120 in vivo, we have generated conditional p120 knockout mouse models for breast, prostate and colon cancer. Interestingly, the mammary gland fails to develop altogether if p120 is knocked out early in the process. In both the prostate and intestine, p120 ablation by itself gives rise to tumors in 40% or more of the mice. In the intestine, p120 also appears to be linked to the tumor suppressor adenomatous polyposis coli (APC). The latter observation may have important clinical implications, as APC mutation is responsible for over 85% of human colon cancer. These results illustrate directly that p120 downregulation can lead to tumorigenesis in mice.

The laboratory continues to examine underlying mechanisms by cell and molecular approaches. Previously, we showed that p120 suppresses RhoA activity downstream of Rac1 and Src and is required for anchorage independent growth induced by these oncogenes. In addition, p120 interacts physically and functionally with Kaiso, a BTB/POZ domain protein involved in transcriptional repression. We are currently pursuing these and several new leads relevant to novel binding partners and signaling pathways that might explain p120’s role in various cancers.

*For more information on p120, please see recent reviews and references included on this site. Note that the 2007 issue of BBA (volume 1773) is devoted entirely to reviews on p120 and its family members, and contains an historical perspective written by Dr. Reynolds on the discovery of p120 and it's role(s) with respect to Src, cadherin function, and Kaiso.

Publications:

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