Focal adhesion kinase: Insight into its roles and therapeutic potential in oesophageal cancer

ABSTRACT Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase whose focal adhesion targeting (FAT) domain interacts with other focal adhesion molecules in integrin-mediated signaling. Localization of activated FAK to focal adhesions is indispensable for its function. Here we describe a solution structure of the FAT domain bound to a peptide derived from paxillin, a FAK-binding partner. The FAT domain is composed of four helices that form a “right-turn” elongated bundle; the globular fold is mainly maintained by hydrophobic interactions. The bound peptide further stabilizes the structure. Certain signaling events such as phosphorylation and molecule interplay may induce opening of the helix bundle. Such conformational change is proposed to precede departure of FAK from focal adhesions, which starts focal adhesion turnover.

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Focal Adhesion Kinase: Insight into Molecular Roles and Functions in Hepatocellular Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms18010099 ◽

2017 ◽

Vol 18 (1) ◽

pp. 99 ◽

Cited By ~ 23

Author(s):

Nadia Panera ◽

Annalisa Crudele ◽

Ilaria Romito ◽

Daniela Gnani ◽

Anna Alisi

Keyword(s):

Hepatocellular Carcinoma ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Insight Into

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Structural features of the focal adhesion kinase-paxillin complex give insight into the dynamics of focal adhesion assembly

Protein Science ◽

10.1110/ps.041107205 ◽

2005 ◽

Vol 14 (3) ◽

pp. 644-652 ◽

Cited By ~ 34

Author(s):

Craig M. Bertolucci ◽

Cristina D. Guibao ◽

Jie Zheng

Keyword(s):

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Structural Features ◽

Insight Into

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Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response

Endocrine Related Cancer ◽

10.1530/erc-13-0019 ◽

2013 ◽

Vol 20 (5) ◽

pp. 691-704 ◽

Cited By ~ 20

Author(s):

Glorianne Lazaro ◽

Chris Smith ◽

Lindy Goddard ◽

Nicola Jordan ◽

Richard McClelland ◽

...

Keyword(s):

Breast Cancer ◽

Cell Growth ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Therapeutic Potential ◽

Specific Inhibitor ◽

Predictive Marker ◽

Clinical Effectiveness ◽

Limiting Factor ◽

Her2 Breast Cancer

The HER2 transmembrane receptor is a well-characterised predictive marker for trastuzumab benefit and may be associated with decreased benefit from endocrine therapy use. Despite the clinical effectiveness of anti-HER2 agents in such cases, resistance represents a significant limiting factor. Focal adhesion kinase (FAK) plays an important role in HER2 signalling, mediating downstream Akt activation in addition to HER2 cross talk with other growth factor receptors. In this study, we investigated the therapeutic potential of FAK in oestrogen receptor-positive (ER+)/HER2+ breast cancer using the novel FAK-specific inhibitor PF4554878 (‘PF878’). The activation of the FAK/HER2 signalling pathway was assessed in ER+/HER2− (MCF7 and T47D) and ER+/HER2+ (BT-474 and MDAMB361) breast cancer cells in the presence or absence of PF878 and PF878±trastuzumab. The effects of PF878 on cell growth as a monotherapy and in combination with trastuzumab were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Coulter counting with isobologram analysis to determine synergy/additive effects. FAK activation (at Y861 but not at Y397) was highest in ER+/HER2+ cells, which also demonstrated the greatest sensitivity to PF878. As a monotherapy, PF878 prevented heregulin-induced MDA361 cell migration, but had no significant effect on cell growth. The treatment of ER+/HER2+ cells with PF878 and trastuzumab in combination resulted in the synergistic inhibition of cell proliferation. Underlying this was an abrogation of Akt activity and increased poly(ADP-ribose) polymerase cleavage, effects that were greatest in trastuzumab-refractory MDA361 cells. Collectively, these data support a role for FAK in ER+/HER2+ breast cancer, where its targeting has the potential to improve trastuzumab response. This is particularly important in the context of ER+/HER2+, trastuzumab-refractory disease, where FAK inhibition may present an important strategy to restore trastuzumab sensitivity.

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Early signalling events of autophagy

Essays in Biochemistry ◽

10.1042/bse0550001 ◽

2013 ◽

Vol 55 ◽

pp. 1-15 ◽

Cited By ~ 16

Author(s):

Laura E. Gallagher ◽

Edmond Y.W. Chan

Keyword(s):

Protein Kinase ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Mammalian Cells ◽

Mammalian Target Of Rapamycin ◽

Interacting Protein ◽

The Core ◽

Autophagy Gene ◽

Autophagy Induction ◽

Cellular Pathways

Autophagy is a conserved cellular degradative process important for cellular homoeostasis and survival. An early committal step during the initiation of autophagy requires the actions of a protein kinase called ATG1 (autophagy gene 1). In mammalian cells, ATG1 is represented by ULK1 (uncoordinated-51-like kinase 1), which relies on its essential regulatory cofactors mATG13, FIP200 (focal adhesion kinase family-interacting protein 200 kDa) and ATG101. Much evidence indicates that mTORC1 [mechanistic (also known as mammalian) target of rapamycin complex 1] signals downstream to the ULK1 complex to negatively regulate autophagy. In this chapter, we discuss our understanding on how the mTORC1–ULK1 signalling axis drives the initial steps of autophagy induction. We conclude with a summary of our growing appreciation of the additional cellular pathways that interconnect with the core mTORC1–ULK1 signalling module.

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