Overexpression of FAK transcripts is crucial for FAK-mediated tumor cell function. The PTK2 promoter is also activated or made more active by the transcription factors NF-κB (Corsi et al., 2006), BACH1 (Xie et al., 2022), ETV1 (Zhang et al., 2022), ETS1 (Tomar et al., 2018), NANOG (Ho et al., 2012), AGO2 (Cheng et al., 2013), and ETV4 (Li et al., 2013), which similarly increases the expression of FAK mRNA. In contrast, P53 (Cance and Golubovskaya, 2008) and ATF3 (Tian et al., 2021) limit some of the tumor’s functions by lowering the activity of the PTK2 promoter and the number of transcripts. By directly increasing PTK2 and IGF1R in hepatocellular carcinoma cells, BACH1 speeds up the development and spread of Hepatocellular carcinoma (HCC) (Xie et al., 2022). Additionally, HCC patients with ETV1/PTK2 or ETV1/c-MET co-positive hepatocellular carcinoma in two different cohorts had a worse prognosis. ETV1 can enhance HCC metastasis in HCC by upregulating PTK2 and MET (Zhang et al., 2022). ETS1, a crucial transcription factor produced by the microenvironment in ovarian cancer cells, predicts a poor prognosis and targets PTK2 while promoting graft colonization by increasing FAK transcript levels (Tomar et al., 2018). In colon cancer cells, NANOG increases FAK expression, and FAK’s phosphorylation is a component of the signaling loop that increases NANOG activity (Ho et al., 2012). AGO2 is a component of the cellular RNA interference apparatus that is increased in hepatocellular carcinoma and stimulates FAK transcription (Cheng et al., 2013). In mice, inhibiting AGO2 lowers FAK levels while preventing tumor development and metastasis. ETV4 induced FAK expression in vitro, again considering its role as a transcription factor affecting PTK2 promoter activity (Li et al., 2013). ATF3 is a downstream transcription factor of ROS, and increased levels of ATF3 can reduce the transcriptional level of FAK, reducing prostate cancer cells’ invasiveness (Tian et al., 2021). In non-coding RNA studies, CircC16orf62 was found to act as a molecular sponge for miR-138-5p and a competitive endogenous RNA for PTK2, which promotes the activation of the downstream AKT/mTOR pathway (Zhang et al., 2021b). Hypomethylation of the FAK promoter region was also associated with the high expression of FAK in HCC (Fan et al., 2019).

Selective splicing of mRNA (Alternative Splicing, AS) enhances the fine-tuning of protein function. By generating from an initial unique pre-messenger RNA, different protein isoforms varying in expression, subcellular localization, interactions and activities, AS represents a critical player in protein function regulation in development, physiology and disease (Kelemen et al., 2013). It was found that FAK mRNA showed three different alternative splice variants in colorectal cancer, namely FAK⁰, FAK²⁸, and FAK⁶, and was associated with the invasive ability of colorectal cancer (Devaud et al., 2019). In papillary thyroid carcinoma, the number of FAK³³ variants was elevated and positively correlated with total FAK transcripts and pY397-FAK protein levels, as well as with the advanced features of papillary thyroid carcinoma (Ignjatović et al., 2022). After comparing breast cancer tissues with normal tissues, FAK²⁶ was a spliceosome expressed only in breast cancer tissues and allowed FAK proteins to acquire resistance to caspase-mediated cleavage (Yao et al., 2014). For this AS, it has been demonstrated that circRPAP2 may attenuate the selective splicing of PTK2 by competing with PTK2 pre-mRNA for binding to the RRM1 structural domain of SRSF1 (Yu and Fang, 2022).

FAK activation is mainly controlled by FAK dimerization, intramolecular inhibition of the FERM structural domain, FAK phosphorylation and other mechanisms. The most typical mechanism that promotes FAK activation involves the aggregation of integrin receptors upon cell binding to extracellular matrix (ECM) proteins, a process that involves FAK dimerization. The dimerization is formed by binding of the n-terminal FERM structural domain of FAK and is stabilized by the interaction of the FERM and c-terminal FAT structural domains. FAT binds to the basic motif on FERM that regulates coactivation and nuclear localization (Brami‐Cherrier et al., 2014). This leads to autophosphorylation of FAK at the Y397 site, binding of Src family kinases to the phosphorylation site, and mediates phosphorylation of the FAK kinase structural domain activation loop to form an activated FAK - Src complex (Lietha et al., 2007). In addition to Src, RET can also phosphorylate residues of Tyr576 and Tyr577 to activate FAK (Plaza-Menacho et al., 2011). Experiments using fluorescent biosensors have shown that when ECM binds or interacts with phosphatidylinositol lipids, the FERM structural domain undergoes conformational changes that unwind the self-inhibitory interactions (Goñi et al., 2014). Enhancing the stiffness or tension associated with cell- ECM interactions by strengthening integrin signaling has also been shown to promote FAK activation (Bauer et al., 2019), which is essential not only for mechanotransduction but also critical for tumor progression. In addition to binding partners to accelerate conformational changes in the FERM structural domain, growth factor receptors, such as MET, epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR), can also phosphorylate Tyr194 to relieve self-inhibition and induce FAK activation (Chen et al., 2011). In addition, Tyr397 phosphorylation is also associated with FAK activity. SHP2 is responsible for the dephosphorylation of pTyr397 and inhibits FAK activity (von Wichert et al., 2003). Phosphorylation-dependent isomerization of protein tyrosine phosphatase (PTP)-PEST promotes the interaction of PTP-PEST with FAK and the dephosphorylation of the Tyr397 site on FAK, leading to FAK inactivation (Zheng et al., 2011). SHP2 and PTP-PEST synergistically control FAK activity with Src and promote the kinetics of focal adhesion complexes, thereby facilitating cell motility (Wu et al., 2015; Chuang et al., 2021).

Lung cancer is a malignant tumor with high morbidity and mortality rates. As early as 1996, phosphorylated FAK was shown to be a significant component of 100–130 kDa phosphorylated proteins in lung surgery specimens and was associated with poor patient prognosis (Nishimura et al., 1996). Increased FAK phosphorylation is strongly associated with lymph node metastasis and disease-free survival in tumors (Imaizumi et al., 1997). Smoking is an important environmental factor in lung cancer, and a recent study confirmed that smoking activates the c-Src/FAK pathway (Stading et al., 2021), subsequently promoting lung carcinogenesis and progression (Zhou et al., 2019), drug resistance (Kang et al., 2013), and maintenance of KRAS-driven lung adenocarcinoma (Zhou et al., 2018). This provides ample evidence that the role of FAK in lung cancer cannot be ignored.

Lung cancer is pathologically divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC accounts for approximately 10% and has a poorer prognosis than NSCLC. Recent studies on the differences in FAK and p-FAK expression in SCLC and NSCLC have shown that the staining scores of FAK and p-FAK were significantly higher in lung cancer and SCLC tissues than in normal lung and NSCLC tissues (Aboubakar Nana et al., 2019b). There are many subtypes of NSCLC, such as lung squamous carcinoma, lung adenocarcinoma, and large cell lung cancer. FAK overexpression in NSCLC was associated with the stage as well as the adenocarcinoma subtype and positively correlated with lymph node metastasis (Ji et al., 2013). Whether there is a link between FAK expression and NSCLC prognosis is unclear and may be ethnically relevant (Ji et al., 2013; Dy et al., 2014; Aboubakar Nana et al., 2019b).

Although FAK appears to be more relevant in SCLC, most in vitro experiments have been conducted on NSCLC. Consistent with these pathological features, Fu et al. (2015) found that in NSCLC cells, ENO1 could enhance the proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and glycolytic capacity of tumor cells by activating the FAK/PI3K/AKT pathway. Moreover, depletion of FAK using siRNA inhibited the phosphorylation of molecules such as Src, ERK1/2, PI3K, and Akt (Fu et al., 2015). Additionally, Wang et al. (2020a) found that secretory PKM2 directly binds to integrin β1 and activates the FAK/SRC/ERK axis to promote lung cancer metastasis. Fu et al. (2020) also found that secretory OPN leads to acquired epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance by activating the integrin αVβ3/FAK pathway, which provides novel insights for the application of FAK inhibitors in lung cancer treatment.

The role of FAK in cell cycle progression has been reported previously. The gene encoding cyclin D1, a key regulator of G1/S phase progression, is the major target of FAK action in cell cycle control. Zhao et al. (1998) and Zhao et al. (2001) found that FAK could regulate cyclin D1 gene expression mediated by the ERK1/2 pathway at the EtsB-binding site (Njei et al., 2015). Expression of the autophosphorylation site-mutated FAK molecule (FAK-397F) in glioblastoma cells leads to exit from the G1 phase by decreasing the expression of cyclinD1 and E and enhancing the expression of p27 (Kip1) and p21 (Waf1) (Ding et al., 2005). In particular, in a mouse model, Marta et al. found that intranuclear FAK regulation, which is dependent on IGFBP3 transcription, regulates squamous cell carcinoma cell cycle progression and tumor growth in vivo and that FAK interacts with many RUNX1 regulatory proteins (Canel et al., 2017). Moreover, Zhang et al. (2019) found that MET/FAK signaling enables CDK4/6 non-dependent CDK2 activation, which leads to cell cycle delivery. Furthermore, they found that the inhibition of CDK4/6 and MET/FAK can synergistically alter the fate of tumor cells.

FAK is associated with apoptosis in cancer cells. First, FAK inhibition can lead to the loss of adhesion and apoptosis of tumor cells, which has been confirmed at an early stage (Xu et al., 1996; Xu et al., 2000). Sonoda et al. (2000) demonstrated that FAK induces IAPs by activating the PI3K/Akt pathway along with NF-κB. This ultimately inhibits apoptosis by inhibiting the caspase-3 cascade. RIP, a major component of the death receptor complex, mediates apoptosis by interacting with Fas and tumor necrosis factor receptor 1 by binding to junctional proteins. The pro-apoptotic signal provided by RIP is inhibited by its binding to FAK (Kurenova et al., 2004). In addition, the FERM structural domain of nuclear FAK interacts with the N-terminal structural domain of wild-type p53 and MDM-2 to promote the degradation of p53, thereby preventing apoptosis (Lim et al., 2008; Golubovskaya and Cance, 2011).

One reason for the crucial role of FAK in promoting tumor proliferation is that FAK can promote cell survival in suspension, also known as anoikis apoptosis resistance, first identified by Frisch et al. (1996). In the death receptor-mediated mechanism of anoikis, the dissociation of FAK and receptor-interacting protein (RIP) leads to the binding of RIP to FAS. This forms a death-inducing signaling complex (DISC) that activates caspase-3. Indeed, activation of the FAK/Src complex is focused on the upregulation of signaling cascades (including PI3K-Akt, ERK1/2, and other mitogen-activated protein kinases) which maintain cell survival by promoting the resistance of isolated cells to “anoikis”. In addition, the combination of FAK and RIP enhances anoikis resistance by inhibiting the binding of RIP to Fas and the formation of the death signaling complex, which allows cells to escape anoikis.

FAK expression drives the establishment of an immunosuppressive TME by increasing the expression of various chemokines. It has been found that nuclear FAK increases the expression of homing signals (Huehn and Hamann, 2005; Ondondo et al., 2013), such as CCL5, CCL7, CXCL10, and TGFβ2, which are chemokines and cytokines associated with the recruitment of regulatory T cells (Tregs) (Serrels et al., 2015). This suggests that FAK activation in cancer cells plays a critical role in regulating the tumor immune landscape. FAK also enhances the expression of IL-33 (Griffith et al., 2021), and the FAK-IL-33 complex can increase the transcription of chemokine genes by interacting with CCL5 transcriptional regulators. It can also enhance the suppressive activity of Treg cells by interacting with ST2L on the surface of immune cells, thereby promoting tumor growth (Schiering et al., 2014). Alternatively, it activates the cytotoxic function of CD8⁺ T cells, resulting in improved antitumor immunity (Yang et al., 2011). FAK depletion results in the regression of CD80-expressing tumors by increasing the number of CD28⁺ T cells within the TME (Canel et al., 2020). LysM-Cre was used to knock out FAK in mononuclear phagocytes in an MMTV-polyoma middle T murine model of breast cancer, and knockout myeloid cells were found to show faster tumor growth. Increased tumor size was associated with a decrease in the number of natural killer cells, suggesting that FAK expression in myeloid cells correlates with the recruitment or survival of natural killer cells in the TME (Llewellyn et al., 2018).

FAK has been shown to play a key role in tumor angiogenesis in multiple in vivo mouse models (Tavora et al., 2010; Kostourou et al., 2013). FAK in endothelial cells initiates angiogenesis, and FAK deletion reduces VEGF- and bFGF-induced angiogenesis (Tavora et al., 2010), which may be achieved through the FAK/Src/PI3K(P55)/Akt axis (Pedrosa et al., 2019). FAK affects angiogenesis and is mainly associated with Tyr397 and Tyr861 (Kostourou et al., 2013). Endothelial cell-specific expression of the FAK Y397F mutant reduces tumor angiogenesis (Pedrosa et al., 2019), where FAK affects VEGFR2 transcription through its kinase activity (Sun et al., 2018b; Shiau et al., 2021). This has also been demonstrated in recent studies, where phosphorylated Try397-FAK was found to be an important part of angiogenesis promotion in experiments in which protrudin (Arora et al., 2022) and HAX1 (You et al., 2022) affected angiogenesis. Try397-FAK can affect angiogenesis via ERG (D'Amico et al., 2022). In a subcutaneous Lewis lung cancer tumor model, only mice with pericyte-specific FAK-Y861F mutation showed reduced angiogenesis and tumor growth. This is associated with a notable increase in vascular degeneration (Lees et al., 2021). In addition, the detection of secretion and protein expression of FAK-Y861F pericytes revealed that cytokines and proteins promote tumor cell apoptosis and increased secretion (Lees et al., 2021). Therefore, pericyte FAK-Y861F plays a role in controlling tumor growth (Lees et al., 2021), and pericyte FAK deficiency increases tumor growth and angiogenesis (Lechertier et al., 2020a). Interestingly, when studying the specific mechanism by which FAK phosphorylation at Tyr397 and Tyr861 regulates tumor angiogenesis, it was found that FAK ^Y397F/Y397F and FAK ^Y861F/Y861F mice had different end-stage tumor vascular responses. This may be due to the enhanced p190Rhogef/p130Cas dependent signal of FAK-Y861F rather than FAK-Y397F (Pedrosa et al., 2019). Furthermore, pericyte FAK deletion enhances Gas6-stimulated phosphorylation of the receptor tyrosine kinase Axl and upregulates Cyr61, while pericyte-derived Cyr61 indicates that tumor cells upregulate the expression of the pro-angiogenic/tumorigenic transmembrane receptor tissue factor (Lechertier et al., 2020b). In addition to being a vascular signal, endothelial FAK is a regulatory site for tumor chemoradiotherapy sensitivity (Roy-Luzarraga and Hodivala-Dilke, 2016). FAK also affects ECM by promoting vascular permeability (Lee et al., 2010; Chen et al., 2012), thereby increasing the probability of tumor metastasis (Jean et al., 2014).

Lymphopenia and immunocytotoxicity are also associated with metastasis (Mlecnik et al., 2016). FAK reduces lymphocyte toxicity and affects lymphatic vessel formation (Morita et al., 2015). Among the known lymphangiogenic factors, vascular endothelial growth factor-C (VEGF-C) is the best characterized and recognized as a major regulator of lymphangiogenesis. It reshapes the lymphatic microenvironment by regulating the production of chemokines in lymphatic endothelial cells (Chen et al., 2019). FAK affects VEGF-C production via various signaling pathways. For example, FAK inhibition can reduce IL-6-induced VEGF-C expression and VEGF-C promoter luciferase activity (Huang et al., 2016a). Leptin-induced VEGF-C is mediated by the FAK/PI3K/Akt signaling pathway and negatively regulates the expression of microRNA-27b (Yang et al., 2016). The expression level of Nrp2 in tumor-associated lymphatic endothelial cells in colorectal cancer is significantly correlated with tumor lymphatic density. Nrp2 promotes tumor lymphangiogenesis through the integrin α9β1/FAK/Erk pathway rather than the VEGF-C/VEGFR3 signaling pathway (Ou et al., 2015).

Based on FAK signaling, the metabolic relationship between the ECM and the tumor is mutual. The absence of FAK in CAFs leads to enhanced glycolysis in malignant cells because FAK deletion in CAFs increases the production of chemokines CCL6 and CCL12. This in turn activates protein kinase A through CCR1/CCR2 in cancer cells (Demircioglu et al., 2020). At the same time, adipose tissue in obesity can also induce the activation of tumor FAK signaling by secreting chemokines or fatty acids and change tumor invasiveness and lipid metabolism (Blücher et al., 2020). Desmosplasia is a characteristic of most solid tumors in which PI3K plays a vital role, affecting tumor development. PI3K activation occurs when increased matrix stiffness is triggered through integrin-mediated FAK and its downstream pathway (Kallergi et al., 2007; Provenzano et al., 2008; Tung et al., 2015). The regulation of PIP3 by PI3K and the subsequent activation of Akt and mTOR are the means of remodeling the tumor environment. Through this medium, desmosplasia and increased ECM deposition affect cell metabolism, promoting cell proliferation and survival (Wozniak et al., 2003) as well as carcinogenic transformation and tumor metastasis (Levental et al., 2009). It is also the main cause of acquired chemoresistance (Darvishi et al., 2022). Therefore, FAK plays a significant role in physical construction of the TME.

After blocking FAK with siRNA and inhibitors, glucose uptake and glycolysis in glioblastoma multiforme cells were inhibited, but mitochondrial function was significantly enhanced (Che et al., 2021). In addition, fat-selective loss of FAK leads to impaired glucose tolerance and insulin sensitivity (Luk et al., 2017). Growth factors, such as insulin/IGF-1 and anchorage, are the primary extracellular cues that stimulate cell proliferation. FAK interactions with IGF1R (Kasprzak, 2021) and integrins (Che et al., 2021) transmit these growth signals by activating effectors, such as PI3K/Akt, promoting glucose consumption to fuel rapid growth of tumor cells. The N-terminal FERM structural domain of FAK binds directly to the IGF1R (Stanicka et al., 2018), leading to the activation of PI3K/Akt (Godoy-Parejo et al., 2019) and YAP (Rigiracciolo et al., 2020) signaling. Inhibition of the FAK-IGF1R interaction by small molecules induces apoptosis and inhibits tumor growth (Lehman et al., 2021). Impaired non-dependent biological functions of IGF1R kinase lead to a decrease in intracellular glucose levels, resulting in decreased cancer cell viability (Wang et al., 2022). Likewise, integrins are among the reinforcing factors in the Warburg effect of tumors (Yousefi et al., 2021). Studies have shown that FAK is a downstream effector of integrin αV/β3 and regulates the metabolic changes in glioblastoma cells to glycolysis (Che et al., 2021). CD81 can interact with integrins αV/β1 and αV/β5 to form a complex that mediates irisin-induced FAK signal transduction, and subsequently regulates the growth and energy balance of beige fat progenitor cells (Oguri et al., 2020). Twist, a key regulator of EMT, enhances aerobic glycolysis by activating β1-integrin/FAK/PI3K/AKT/mTOR and inhibiting P53 signaling (Yang et al., 2015). ECM1 significantly increased the uptake of 18^F-deoxyglucose by xenografts, and further studies have found that ECM1 interacts with integrin β4 and induces the expression of the transcription factor SOX2 through the integrin β4/FAK/glycogen synthase kinase 3β/HIF-1α pathway. This changes the gene expression of EMT factors and glucose metabolism-related enzymes (Gan et al., 2018).

In addition, CTGF promotes aerobic glycolysis via the FAK/Src/NF-κB p65/Glut3 pathway (Kim et al., 2021). Hexokinase 2 (HK2) is highly expressed in ascites and metastases in patients with ovarian cancer. It is the first key enzyme to be involved in glucose metabolism. HK2 overexpression can regulate lactate production through the expression of MMP9/Nanog/Sox9 mediated by the FAK/ERK1/2 signaling pathway and participates in ovarian cancer metastasis and stem cell regulation (Siu et al., 2019).

As the key regulator of de novo lipid synthesis, fatty acid synthase (FASN) is highly expressed in many tumors. Inhibition of FASN reduces the activity of p-FAK, indicating that FAK may contribute to changes in the invasive phenotype of tumor cells caused by metabolic reprogramming (Jafari et al., 2019). Additionally, inhibition of critical lipogenic enzymes ACLY and FAS results in the reduction of FAK, Akt, and paxillin activity and cell viability (Zaytseva et al., 2012).

FAK expression is related to glutamine metabolism, which may mediate changes in glutamine metabolism through the PI3K/Akt pathway, thus playing a role in cell autophagy, stress, and growth (Zhang and Hochwald, 2014). FAK stimulates PI3K/Akt signaling, whereas PI3K/Akt activation increases the levels of glutamine and its synthetase (Van Der Vos et al., 2012). The YAP/TAZ pathway plays an important role in amino acid metabolic reprogramming (Jeon et al., 2022), and FAK/Src signaling has been shown to mediate the activation of YAP/TAZ signaling in tumor cells (Totaro et al., 2018; Ma et al., 2020). However, there are still questions regarding the specific mechanisms of FAK in amino acid metabolic reprogramming, such as whether it affects the expression of key enzymes and whether there are key signaling pathways.

Whether FAK has a core pathway and function through the metabolism of the three nutrients remains to be investigated, which is an important part of future research on the Warburg effect (Figure 5).