Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis

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Abstract

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays critical roles in integrin-mediated signal transductions and also participates in signaling by other cell surface receptors. In integrin-mediated cell adhesion, FAK is activated via disruption of an auto-inhibitory intra-molecular interaction between its amino terminal FERM domain and the central kinase domain. The activated FAK forms a complex with Src family kinases, which initiates multiple downstream signaling pathways through phosphorylation of other proteins to regulate different cellular functions. Multiple downstream signaling pathways are identified to mediate FAK regulation of migration of various normal and cancer cells. Extensive studies in cultured cells as well as conditional FAK knockout mouse models indicated a critical role of FAK in angiogenesis during embryonic development and cancer progression. More recent studies also revealed kinase-independent functions for FAK in endothelial cells and fibroblasts. Consistent with its roles in cell migration and angiogenesis, increased expression and/or activation of FAK are found in a variety of human cancers. Therefore, small molecular inhibitors for FAK kinase activity as well as future development of novel therapies targeting the potentially kinase-independent functions of FAK are promising treatments for metastatic cancer as well as other diseases.

Introduction

Cell migration plays crucial roles not only in a various biological processes such as embryonic development, but also in different diseases including cancer and cardiovascular disorders [1], [2]. Cell migration is a dynamic and multistep process of leading edge protrusion, turnover of focal adhesions, generation of tractional forces, and tail retraction and detachment [3], [4]. As the major cellular receptors for extracellular matrix (ECM), integrin family cell adhesion receptors are essential for each of these steps in cell migration [5]. Although they have relatively short cytoplasmic domains, integrins regulate cell migration as well as other cellular functions through their coupling to multiple cytoskeletal and signaling molecules, many of which co-cluster with integrins in focal adhesions in adherent cells. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is the earliest identified and one of the most prominent signaling molecules among these proteins [6], [7], [8], [9], [10].

FAK was discovered by two converging lines of research in the early '90 s. In the first, an approximately 120 kDa protein was found as a major integrin-dependent tyrosine phosphorylated protein localized in focal adhesions [11], [12]. In another set of studies, several potential substrates of the v-Src oncogenes were described based on their high tyrosine phosphorylation in transformed cells by v-Src [13]. One of these substrates was soon found to be a tyrosine kinase itself and identical to the 120 kDa protein whose phosphorylation was triggered by integrin-mediated cell adhesion [14], [15]. This protein was named as FAK based on its prominent localization in the focal adhesions [14]. Since these early reports implicating FAK in anchorage-independent growth of cancer cells [15], numerous studies in the last 20 years have established FAK as a central mediator of integrin signaling as well as important components of signaling by other cell surface receptors. In particular, regulation of cell migration by integrin signaling through FAK is well established in many cell types which contribute to pathogenesis of cancer and other diseases [16], [17]. As such, FAK is considered a promising therapeutic target for treatment of cancer and cardiovascular diseases as well as potentially other diseases. Indeed several small molecule inhibitors for FAK have already been developed by different pharmaceutical companies for clinical trials [18], [19], [20]. In this review, we will focus on the roles of FAK and its downstream signaling pathways in cell migration and angiogenesis, as well as recent findings of the kinase-independent functions of FAK which will be important in future considerations to develop therapies targeting FAK. For a more comprehensive perspective on FAK signaling in other cellular functions and developmental and disease processes, the readers are referred to a number of other excellent review articles [6], [7], [8], [9], [10].

Section snippets

Structural features of FAK and its activation by integrins

The FAK gene is highly conserved with over 90% sequence identity across different species including human, mouse, chicken and Xenopus [14], [21], [22], [23]. It has been mapped to human chromosome 8 and mouse chromosome 15, respectively [24]. FAK is composed of a central kinase domain flanked by an N-terminal FERM (Band 4.1, ezrin–radixin–moesin) domain and a C-terminal domain that includes the focal adhesion targeting (FAT) sequence (Fig. 1). The FERM domain of FAK shares similar structure

Regulation of cell migration by FAK signaling pathways

Integrin signaling through FAK has been shown to promote cell migration in numerous studies. Initial suggestion for a role for FAK in cell migration was based on correlative observations of increased expression or activation of FAK in the migrating keratinocytes in epidermal wound healing or ECs migrating into the wounded monolayer in vitro, respectively [42], [43]. Increased levels of FAK expression have also been correlated with the invasive and metastatic potential of several human tumors

Critical roles of FAK signaling in angiogenesis

Early observations that FAK regulates EC migration suggested its potential role in angiogenesis, as migration and invasion of ECs are integral to the process of angiogenesis. This is further supported by the patterns of FAK expression in the developing vasculature during embryogenesis [69]. Moreover, FAK gene knockout in mouse caused early embryonic lethality with extensive cardiovascular defects [46]. Additional support for a role of FAK in angiogenesis includes data suggesting regulation of

FAK possesses both kinase-dependent and -independent functions

Although a few direct substrates have been identified for FAK, the majority of studies so far indicate that an important role of FAK is to mediate tyrosine phosphorylation of proteins by Src family kinases in FAK/Src complex. In another word, FAK was found to function as a scaffold in various signaling events regulating different cellular functions [18], [83], [84], [85]. Nevertheless, since the binding motif for Src is dependent on Y397, which is an autophosphorylation site for FAK, it can be

Concluding remarks: FAK as a target molecule of cancer therapy

As an important regulator of cell migration and angiogenesis, FAK is likely a suitable target for a variety of diseases that are highly dependent on these biological processes. A particularly good case can be made for cancer metastasis, which is driven by both of these processes. It has been well established that solid tumor growth and survival require a well-functioning vascular network, which enables rapid proliferation of tumor cells by the delivery of oxygen and other nutrients and

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