Abstract
A key hallmark of cancer cells is the loss of positional control over growth and survival. Focal adhesion kinase (FAK) is a tyrosine kinase localised at sites of integrin-mediated cell adhesion to the extracellular matrix. FAK controls a number of adhesion-dependent cellular functions, including migration, proliferation and survival. Although FAK is overexpressed and activated in metastatic tumours, where it promotes invasion, it can also be elevated in cancers that have yet to become invasive. The contribution of FAK to the early stages of tumourigenesis is not known. We have examined the effect of activating FAK in non-transformed mammary epithelial cells (MECs) to understand its role in tumour initiation. In agreement with previous studies, we find FAK activation in 2D-culture promotes proliferation, migration, and epithelial-to-mesenchymal transition. However in 3D-cultures that better resemble normal tissue morphology, mammary cells largely respond to FAK activation via suppression of apoptosis, promoting aberrant acinar morphogenesis. This is an acquired function of FAK, because endogenous FAK signalling is not required for normal morphogenesis in 3D-culture or in vivo. Thus, FAK activation may facilitate tumour initiation by causing resistance to apoptosis. We suggest that aberrant FAK activation in breast epithelia is dependent upon the tissue context in which it occurs.
Highlights
A hallmark of cancer is the loss of the normal positional control over cell proliferation, differentiation and apoptosis [1]
MCF10A cells were infected with pCDH-lentivirus expressing turbo GFP (tGFP) alone or myrFAK along with tGFP, and stably-expressing cells were selected by fluorescence-activated cell sorting (FACS)
In two dimensional (2D)-culture, Focal adhesion kinase (FAK) is required for proliferation and migration, and its aberrant activation drives epithelial to mesenchymal transition (EMT)-like changes in non-transformed mammary epithelial cells (MEC)
Summary
A hallmark of cancer is the loss of the normal positional control over cell proliferation, differentiation and apoptosis [1]. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase and adapter molecule that coordinates signalling pathways downstream of integrinmediated adhesion to the extracellular matrix (ECM) [2]. FAK is recruited to integrin-based complexes in adherent cells, where autophosphorylation on tyrosine 397 (Tyr397) allows FAK to form a complex with Src-family kinases. The subsequent Src-dependent phosphorylation of FAK on other tyrosine residues, along with sites on FAK-associated scaffold proteins such as p130CAS and paxillin, results in downstream signalling that regulates proliferation, differentiation and apoptosis. It is not surprising that aberrant FAK signalling has been implicated cancer [3]. There has been considerable interest in developing small molecule inhibitors of FAK
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
