The Anti-Migratory Effects of FKBPL and Its Peptide Derivative, AD-01: Regulation of CD44 and the Cytoskeletal Pathway

Yakkundi, A; McCallum, L; O'Kane, A; Dyer, H; Worthington, J; McKeen, HD; McClements, L; Elliott, C; McCarthy, HO; Hirst, DG; Robson, T

The Anti-Migratory Effects of FKBPL and Its Peptide Derivative, AD-01: Regulation of CD44 and the Cytoskeletal Pathway

Yakkundi, A McCallum, L O'Kane, A Dyer, H Worthington, J McKeen, HD McClements, L

Elliott, C McCarthy, HO Hirst, DG Robson, T

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Publication Type:: Journal Article
Citation:: PLoS ONE, 2013, 8 (2)
Issue Date:: 2013-02-15

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Field	Value	Language
dc.contributor.author	Yakkundi, A	en_US
dc.contributor.author	McCallum, L	en_US
dc.contributor.author	O'Kane, A	en_US
dc.contributor.author	Dyer, H	en_US
dc.contributor.author	Worthington, J	en_US
dc.contributor.author	McKeen, HD	en_US
dc.contributor.author	McClements, L https://orcid.org/0000-0002-4911-1014	en_US
dc.contributor.author	Elliott, C	en_US
dc.contributor.author	McCarthy, HO	en_US
dc.contributor.author	Hirst, DG	en_US
dc.contributor.author	Robson, T	en_US
dc.date.available	2012-12-18	en_US
dc.date.issued	2013-02-15	en_US
dc.identifier.citation	PLoS ONE, 2013, 8 (2)	en_US
dc.identifier.uri	http://hdl.handle.net/10453/127449
dc.description.abstract	FK506 binding protein-like (FKBPL) and its peptide derivatives exert potent anti-angiogenic activity in vitro and in vivo and control tumour growth in xenograft models, when administered exogenously. However, the role of endogenous FKBPL in angiogenesis is not well characterised. Here we investigated the molecular effects of the endogenous protein and its peptide derivative, AD-01, leading to their anti-migratory activity. Inhibition of secreted FKBPL using a blocking antibody or siRNA-mediated knockdown of FKBPL accelerated the migration of human microvascular endothelial cells (HMEC-1). Furthermore, MDA-MB-231 tumour cells stably overexpressing FKBPL inhibited tumour vascular development in vivo suggesting that FKBPL secreted from tumour cells could inhibit angiogenesis. Whilst FKBPL and AD-01 target CD44, the nature of this interaction is not known and here we have further interrogated this aspect. We have demonstrated that FKBPL and AD-01 bind to the CD44 receptor and inhibit tumour cell migration in a CD44 dependant manner; CD44 knockdown abrogated AD-01 binding as well as its anti-migratory activity. Interestingly, FKBPL overexpression and knockdown or treatment with AD-01, regulated CD44 expression, suggesting a co-regulatory pathway for these two proteins. Downstream of CD44, alterations in the actin cytoskeleton, indicated by intense cortical actin staining and a lack of cell spreading and communication were observed following treatment with AD-01, explaining the anti-migratory phenotype. Concomitantly, AD-01 inhibited Rac-1 activity, up-regulated RhoA and the actin binding proteins, profilin and vinculin. Thus the anti-angiogenic protein, FKBPL, and AD-01, offer a promising and alternative approach for targeting both CD44 positive tumours and vasculature networks. © 2013 Yakkundi et al.	en_US
dc.relation.ispartof	PLoS ONE	en_US
dc.relation.isbasedon	10.1371/journal.pone.0055075	en_US
dc.subject.classification	General Science & Technology	en_US
dc.subject.mesh	Cell Line	en_US
dc.subject.mesh	Cytoskeleton	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Actins	en_US
dc.subject.mesh	Tubulin	en_US
dc.subject.mesh	Immunophilins	en_US
dc.subject.mesh	Peptides	en_US
dc.subject.mesh	Antigens, CD44	en_US
dc.subject.mesh	Signal Transduction	en_US
dc.subject.mesh	Cell Movement	en_US
dc.subject.mesh	Gene Expression Regulation	en_US
dc.subject.mesh	Amino Acid Sequence	en_US
dc.subject.mesh	Molecular Sequence Data	en_US
dc.subject.mesh	rho-Associated Kinases	en_US
dc.subject.mesh	Gene Knockdown Techniques	en_US
dc.subject.mesh	Hyaluronan Receptors	en_US
dc.title	The Anti-Migratory Effects of FKBPL and Its Peptide Derivative, AD-01: Regulation of CD44 and the Cytoskeletal Pathway	en_US
dc.type	Journal Article
utslib.citation.volume	2	en_US
utslib.citation.volume	8	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access
pubs.issue	2	en_US
pubs.publication-status	Published	en_US
pubs.volume	8	en_US

Abstract:

FK506 binding protein-like (FKBPL) and its peptide derivatives exert potent anti-angiogenic activity in vitro and in vivo and control tumour growth in xenograft models, when administered exogenously. However, the role of endogenous FKBPL in angiogenesis is not well characterised. Here we investigated the molecular effects of the endogenous protein and its peptide derivative, AD-01, leading to their anti-migratory activity. Inhibition of secreted FKBPL using a blocking antibody or siRNA-mediated knockdown of FKBPL accelerated the migration of human microvascular endothelial cells (HMEC-1). Furthermore, MDA-MB-231 tumour cells stably overexpressing FKBPL inhibited tumour vascular development in vivo suggesting that FKBPL secreted from tumour cells could inhibit angiogenesis. Whilst FKBPL and AD-01 target CD44, the nature of this interaction is not known and here we have further interrogated this aspect. We have demonstrated that FKBPL and AD-01 bind to the CD44 receptor and inhibit tumour cell migration in a CD44 dependant manner; CD44 knockdown abrogated AD-01 binding as well as its anti-migratory activity. Interestingly, FKBPL overexpression and knockdown or treatment with AD-01, regulated CD44 expression, suggesting a co-regulatory pathway for these two proteins. Downstream of CD44, alterations in the actin cytoskeleton, indicated by intense cortical actin staining and a lack of cell spreading and communication were observed following treatment with AD-01, explaining the anti-migratory phenotype. Concomitantly, AD-01 inhibited Rac-1 activity, up-regulated RhoA and the actin binding proteins, profilin and vinculin. Thus the anti-angiogenic protein, FKBPL, and AD-01, offer a promising and alternative approach for targeting both CD44 positive tumours and vasculature networks. © 2013 Yakkundi et al.

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http://hdl.handle.net/10453/127449