Nuclear FAK: a New Mode of Gene Regulation from Cellular Adhesions

Abstract

Focal adhesion kinase (FAK) is a protein tyrosine kinase (PTK) crucial in regulation of cell migration and proliferation. In addition to its canonical roles as a cytoplasmic kinase downstream of integrin and growth factor receptor signaling, recent studies revealed new aspects of FAK action in the nucleus. Nuclear FAK promotes p53 and GATA4 degradation via ubiquitination, resulting in enhanced cell proliferation and reduced inflammatory responses. FAK can also serve as a co-transcriptional regulator that alters a gene transcriptional activity. These findings established a new paradigm of FAK signaling from cellular adhesions to the nucleus. Although physiological stimuli for controlling FAK nuclear localization have not been completely characterized, FAK shuttles from focal adhesions to the nucleus to directly convey extracellular signals. Interestingly, nuclear translocation of FAK becomes prominent in kinase-inhibited conditions such as in de-adhesion and pharmacological FAK inhibition, while a small fraction of nuclear FAK is observed a normal growth condition. In this review, roles of nuclear FAK in regulating transcription factors will be discussed. Furthermore, a potential use of a pharmacological FAK inhibitor to target nuclear FAK function in diseases such as inflammation will be emphasized.

Altered gene expression patterns during the initiation and promotion stages of neonatally diethylstilbestrol-induced hyperplasia/dysplasia/neoplasia in the hamster uterus

“…Focal adhesion kinase (FAK) is a tyrosine kinase that is linked to cell:extracellular matrix (ECM) signaling [43, 44] and may also exert nuclear functions [45] in both normal and neoplastic cells. We observed that FAK staining (Fig.…”

Bone marrow-derived mesenchymal cells feature selective migration behavior on submicro- and nano-dimensional multi-patterned substrates

“…Such processes can in turn have influence on protein expression, protein interaction, local protein concentration, and intracellular signaling, such as in case of the focal adhesion kinase (FAK). FAK, which upon stimulation at the membrane can induce signal-transduction into the nucleus and gene expression [15,18,19], is known to have strong effects on cell adhesion and migration [20]. Previous studies exploiting a similar ''biochip''-setup in our group have indeed shown an effect of topographies on osteoblast focal adhesions [21].…”

Focal Adhesion Kinase-Dependent Role of the Soluble Form of Neurotensin Receptor-3/Sortilin in Colorectal Cancer Cell Dissociation

“…These findings are crucial since the activation of the FAK pathway is described to be involved in survival mechanisms, and especially in a variety of distinct cancer cell lines’ development and metastasis [41,42]. Indeed, FAK regulates numerous downstream intracellular pathways that mediate either cell migration through actin modification [43] or cell proliferation through transcription factors [44]. Interestingly, in HT29 cells, both the actin cytoskeleton and mitogen-activatd protein (MAP) kinases are regulated by sSortilin/NTSR3.…”