Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0017179
Title: HAMLET binding to ?-actinin facilitates tumor cell detachment
Authors: Trulsson M.
Yu H.
Gisselsson L.
Chao Y. 
Urbano A.
Aits S.
Mossberg A.-K.
Svanborg C.
Keywords: alpha actinin
alpha actinin 1
alpha actinin 4
alpha lactalbumin
beta1 integrin
F actin
focal adhesion kinase 1
human alpha lactalbumin made lethal to tumor cell
ion channel
mitogen activated protein kinase 1
small interfering RNA
unclassified drug
actin
actinin
beta1 integrin
cell extract
focal adhesion kinase
HAMLET complex, human
lactalbumin
oleic acid
peptide
amino acid sequence
article
binding site
cell adhesion
cell proliferation
cell structure
cell survival
cell viability
controlled study
enzyme phosphorylation
human
human cell
immunoprecipitation
in vitro study
molecular mechanics
polyacrylamide gel electrophoresis
protein binding
protein cross linking
protein domain
protein expression
protein isolation
protein localization
protein protein interaction
signal transduction
tumor cell
biological model
cell adhesion
cell death
chemical structure
chemistry
drug effect
enzymology
metabolism
molecular genetics
neoplasm
pathology
protein analysis
protein binding
protein transport
tumor cell line
Actinin
Actins
Amino Acid Sequence
Antigens, CD29
Binding Sites
Cell Adhesion
Cell Death
Cell Extracts
Cell Line, Tumor
Cell Survival
Focal Adhesion Protein-Tyrosine Kinases
Humans
Lactalbumin
Models, Biological
Models, Molecular
Molecular Sequence Data
Neoplasms
Oleic Acids
Peptides
Protein Binding
Protein Interaction Mapping
Protein Transport
Signal Transduction
Issue Date: 2011
Citation: Trulsson M., Yu H., Gisselsson L., Chao Y., Urbano A., Aits S., Mossberg A.-K., Svanborg C. (2011). HAMLET binding to ?-actinin facilitates tumor cell detachment. PLoS ONE 6 (3) : e17179. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0017179
Abstract: Cell adhesion is tightly regulated by specific molecular interactions and detachment from the extracellular matrix modifies proliferation and survival. HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) is a protein-lipid complex with tumoricidal activity that also triggers tumor cell detachment in vitro and in vivo, suggesting that molecular interactions defining detachment are perturbed in cancer cells. To identify such interactions, cell membrane extracts were used in Far-western blots and HAMLET was shown to bind ?-actinins; major F-actin cross-linking proteins and focal adhesion constituents. Synthetic peptide mapping revealed that HAMLET binds to the N-terminal actin-binding domain as well as the integrin-binding domain of ?-actinin-4. By co-immunoprecipitation of extracts from HAMLET-treated cancer cells, an interaction with ?-actinin-1 and -4 was observed. Inhibition of ?-actinin-1 and ?-actinin-4 expression by siRNA transfection increased detachment, while ?-actinin-4-GFP over-expression significantly delayed rounding up and detachment of tumor cells in response to HAMLET. In response to HAMLET, adherent tumor cells rounded up and detached, suggesting a loss of the actin cytoskeletal organization. These changes were accompanied by a reduction in ?1 integrin staining and a decrease in FAK and ERK1/2 phosphorylation, consistent with a disruption of integrin-dependent cell adhesion signaling. Detachment per se did not increase cell death during the 22 hour experimental period, regardless of ?-actinin-4 and ?-actinin-1 expression levels but adherent cells with low ?-actinin levels showed increased death in response to HAMLET. The results suggest that the interaction between HAMLET and ?-actinins promotes tumor cell detachment. As ?-actinins also associate with signaling molecules, cytoplasmic domains of transmembrane receptors and ion channels, additional ?-actinin-dependent mechanisms are discussed. © 2011 Trulsson et al.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/162055
ISSN: 19326203
DOI: 10.1371/journal.pone.0017179
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