Integrin-regulated FAK–Src signaling in normal and cancer cells
Introduction
The integrin family of transmembrane receptors link the extracellular matrix (ECM) to the intracellular actin cytoskeleton at points of cell–substratum interaction termed focal adhesions. In addition to this structural role, integrin clustering can initiate intracellular signaling events that promote cell proliferation, survival and migration in both normal and tumorigenic cell contexts [1]. One type of signaling event stimulated by integrins is the tyrosine phosphorylation of cytoskeletal-adaptor and signaling proteins. As integrins do not possess intrinsic catalytic activity, the signals initiated by ECM–integrin interactions are transduced into cells through the activation of integrin-associated proteins. This can occur through co-clustering with receptor protein-tyrosine kinases (PTKs) [2] and here we will cover the integrin-associated signaling connections of non-receptor PTKs with emphasis on focal adhesion kinase (FAK) and Src-family PTKs (SFKs). Recent reviews on FAK–Src signaling have focused on the mechanisms of FAK [3] or Src regulation [4], the interplay between Src and integrins [5], FAK-associated signaling connections in the control of cell motility and invasion [6, 7••] and the roles of FAK or Src in cancer [8]. Here, we will discuss recent developments with regard to FAK–Src signaling with an emphasis on how an integrin linkage to these PTKs controls important aspects of both normal and tumor cell behavior.
Section snippets
Multiple routes for integrin activation of the FAK–Src complex
FAK is primarily recruited to sites of integrin clustering via interactions between its C-terminal domain and integrin-associated proteins such as talin and paxillin (Figure 1). The cytoplasmic tail of β-integrins (β1, β3 and β5) facilitates FAK activation through undefined mechanism(s), potentially involving FAK clustering, autophosphorylation at Y397 [9] and a mechanical linkage of integrins to the actin cytoskeleton [10]. Although point mutations in the FAK N-terminal FERM domain further
The FAK–Src motility-promoting signaling complex
FAK promotes normal and cancer cell migration by regulating focal adhesion formation and turnover through multiple signaling connections (Figure 2). Although phosphorylation of paxillin has been proposed to function as a linkage regulating cell contractility and adhesion disassembly [23], FAK-null fibroblasts exhibit enhanced paxillin phosphorylation and adhesion formation [14•]. However, the tyrosine phosphorylation of the ArfGAP paxillin kinase linker (PKL, also known as G protein-coupled
Integrin connections to FAK in tumorigenesis and cell survival
Whereas mutational inactivation of β1 integrin or FAK expression results in embryonic lethality, conditional inactivation studies are yielding insights into the role of an integrin–FAK signaling linkage in the processes of tumorigenesis [39••, 40••, 41]. In a polyoma middle T (mT) oncogene breast tumor model, loss of β1 integrin expression did not affect mammary gland development, but instead limited the proliferative capacity of mT-transformed tumor cells, with a corresponding decrease in FAK
Uncovering roles for FAK in promoting tumor progression
Several studies have noted that increased FAK expression, enhanced tumor malignancy and poor prognosis correlate with elevated FAK expression [52]. As recently reviewed [53•], Src–FAK signaling promotes E-cadherin internalization during cancer progression, thus facilitating an epithelial-to-mesenchymal transition and enhanced tumor cell motility. Recent studies using transformed FAK-null fibroblasts and RNAi to inhibit FAK expression in carcinoma cells are yielding insights into FAK control of
Novel role for FAK in tumor growth and angiogenesis
Several studies have documented a role for FAK–Src signaling in the control of cell cycle progression in both normal and tumor cells and this is one likely route by which FAK may enhance tumor growth [45, 60]. However, FAK does not function as an oncogene and is not essential for cell proliferation, as demonstrated by the normal growth of FAK−/−p53−/− fibroblasts. In tumorigenic 4T1 breast carcinoma cells, blockage of integrin-stimulated FAK activity or RNAi-mediated reduced FAK expression did
Conclusions
Integrin-mediated activation of FAK and Src regulates various aspects of normal cell behavior and contributes to cancer progression in multiple ways (Figure 4). In normal cells, FAK–Src signals can control cell survival, proliferation and cell motility. Several open questions remain regarding how FAK may act to regulate p53 activity and whether the disruption of this linkage may contribute to increased cell apoptosis in the absence of FAK expression. FAK-null fibroblasts proliferate in cell
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was made possible by grants from the NIH (CA75240, CA87038, CA102310). David Schlaepfer is an Established Investigator of the American Heart Association. This is manuscript number 18343-IMM from The Scripps Research Institute.
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