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Published on: July 26, 2019
Bcr is a substrate for Transglutaminase 2 cross-linking activity
Sun-Ju Yi1, John Groffen, Nora Heisterkamp
1Section of Molecular Carcinogenesis, Division of Hematology/Oncology, Ms#54, Childrens Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles CA 90027, USA.
BMC Biochemistry
|February 12, 2011
Summary
Breakpoint cluster region (Bcr) protein is cross-linked by transglutaminase 2 (TG2) under stress. This TG2 activity targets Bcr, revealing its role beyond non-stressed interactions.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- Breakpoint cluster region (Bcr) protein features a C-terminal GTPase activating protein (GAP) domain for Rac.
- Transglutaminase 2 (TG2) interacts with Bcr's GAP domain, regulating its function.
- TG2's transglutaminase activity is linked to cellular stress responses.
Purpose of the Study:
- To determine if Bcr serves as a substrate for TG2's transglutaminase activity.
- To investigate Bcr modification by TG2 under conditions of cellular stress.
Main Methods:
- In vitro cross-linking assays with purified Bcr and activated TG2.
- Analysis of Bcr mutants and related proteins (Abr) in TG2-mediated cross-linking.
- In vivo studies using human endothelial cells treated with calcium ionophores and cobalt chloride (hypoxia-mimetic).
- Assessment of TG2 inhibitor (cystamine) and proteasome inhibitor effects on Bcr cross-linking.
Main Results:
- Activated TG2 covalently cross-links Bcr, forming high molecular weight complexes.
- A specific N-terminal domain of Bcr (first 62 amino acids) is essential for TG2-mediated cross-linking.
- Endogenous Bcr undergoes TG2-dependent cross-linking in endothelial cells during calcium influx and hypoxia-mimetic stress.
- Cross-linked Bcr localizes to insoluble cellular fractions and is stabilized by proteasome inhibition.
Conclusions:
- Bcr functions as a substrate for TG2 during cellular stress, undergoing covalent cross-linking.
- This TG2-mediated modification of Bcr highlights a novel regulatory mechanism under extreme conditions.
- Bcr acts as both an interaction partner and a direct target of TG2 activity.
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