The cadherin-based adherens junction (AJ) is a critical cell-cell adhesion apparatus, misregulation of which leads to development failures and cancers. The formation of AJs is known to be dependent on the assembly of a local actin network, but the regulation of this remains unclear. Our preliminary data suggest that talin, a protein known for its role in the regulation of the actin network associated with integrin-based cell-matrix adhesion, is also involved in the AJ through a novel talin proteolytic fragment containing the vinculin- and actin- binding domains and a dimerizing region (referred as the VAD fragment). This fragment also undergoes posttranslational arginylation in vivo. We hypothesize that the proteolysis alters the domain architecture of talin, allowing the resulting VAD fragment to localize to the cadherin- based AJ. There the fragment enhances local actin assembly with its functional domains and stabilizes the AJ. Furthermore, arginylation changes the affinities of the VAD fragment to its binding partners and enhances its physiological function in AJs. In this proposed study we will test this hypothesis in these three specific aims: (1) How is the talin VAD fragment recruited to the cadherin-mediated AJ, and how does it enhance actin assembly? (2) Is the formation of cadherin-based AJs dependent on the VAD fragment? (3) How does arginylation enhance the function of the VAD fragment? Through this study, we will elucidate a novel regulatory mechanism for cadherin-based cell-cell adhesions mediated by the novel processing of talin, which was traditionally considered only associated with integrin-based adhesions. Also this project will provide new insight into how the conserved but poorly understood posttranslational arginylation modification affects protein function in cells.

Public Health Relevance

This project will reveal new insights into the regulation of the formation of cell-cell adhesions. As such it is directly relevant to embryo development, tissue formation and regeneration, and pathogenesis and progress of cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM107333-02
Application #
8708163
Study Section
Intercellular Interactions (ICI)
Program Officer
Nie, Zhongzhen
Project Start
2013-08-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$291,650
Indirect Cost
$101,650
Name
University of Miami School of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146