Integrin receptor binding to extracellular matrix proteins generates intracellular signals via enhanced tyrosine phosphorylation events that are important for cell growth, survival, and migration. This review will focus on the functions of the focal adhesion kinase (FAK) protein-tyrosine kinase (PTK) and its role in linking integrin receptors to intracellular signaling pathways. FAK associates with several dierent signaling proteins such as Src-family PTKs, p130Cas , Shc, Grb2, PI 3-kinase, and paxillin. This enables FAK to function within a network of integrin-stimulated signaling pathways leading to the activation of targets such as the ERK and JNK/mitogen-activated protein kinase pathways. Focus will be placed on the structural domains and sites of FAK tyrosine phosphorylation important for FAKmediated signaling events and how these sites are conserved in the FAK-related PTK, Pyk2. We will review what is known about FAK activation by integrin receptor-mediated events and also non-integrin stimuli. In addition, we discuss the emergence of a consensus FAK substrate phosphorylation sequence. Emphasis will also be placed on the role of FAK in generating cell survival signals and the cleavage of FAK during caspase-mediated apoptosis. An in-depth discussion will be presented of integrin-stimulated signaling events occurring in the FAK knockout ®broblasts (FAK À ) and how these cells exhibit de®cits in cell migration. FAK re-expression in the FAK À cells con®rms the role of this PTK in the regulation of cell morphology and in promoting cell migration events. In addition, these results reinforce the potential role for FAK in promoting an invasive phenotype in human tumors. #

†These authors contributed equally to this workHere we show that cells lacking focal adhesion kinase (FAK) are refractory to motility signals from platelet-derived and epidermal growth factors (PDGF and EGF respectively), and that stable re-expression of FAK rescues these defects. FAK associates with activated PDGF-and EGF-receptor (PDGFR and EGFR) signalling complexes, and expression of the band-4.1-like domain at the FAK amino terminus is sufficient to mediate an interaction with activated EGFR. However, efficient EGF-stimulated cell migration also requires FAK to be targeted, by its carboxy-terminal domain, to sites of integrin-receptor clustering. Although the kinase activity of FAK is not needed to promote PDGF-or EGF-stimulated cell motility, kinase-inactive FAK is transphosphorylated at the indispensable Src-kinase-binding site, FAK Y397, after EGF stimulation of cells. Our results establish that FAK is an important receptor-proximal link between growth-factorreceptor and integrin signalling pathways.ransmembrane integrins bind to extracellular matrix proteins and generate important signals that regulate cell proliferation and migration events stimulated by receptors for soluble growth factors. Integrin and growth-factor signalling pathways can interact through several mechanisms, from membrane-proximal clustering of the two receptor types 1,2 to the activation of common downstream signalling pathways [3][4][5] . Although there is a wealth of knowledge regarding the signalling pathways activated by both integrin and growth-factor receptors, little is known about how these signals are integrated by cells and whether there are common receptor-proximal control points that synchronize the execution of biological functions such as cell motility.FAK is a non-receptor protein-tyrosine kinase (PTK) that indirectly localizes to sites of integrin-receptor clustering through Cterminal-domain-mediated interations 6 with integrin-associated proteins such as paxillin 7,8 and talin 9 . FAK becomes phosphorylated at seven to eight different tyrosine residues in vivo after engagement of integrin with matrix proteins 10

Cell migration and invasion are fundamental components of tumor cell metastasis. Increased focal adhesion kinase (FAK) expression and tyrosine phosphorylation are connected with elevated tumorigenesis. Null mutation of FAK results in embryonic lethality, and FAK−/− fibroblasts exhibit cell migration defects in culture. Here we show that viral Src (v-Src) transformation of FAK−/− cells promotes integrin-stimulated motility equal to stable FAK reexpression. However, FAK−/− v-Src cells were not invasive, and FAK reexpression, Tyr-397 phosphorylation, and FAK kinase activity were required for the generation of an invasive cell phenotype. Cell invasion was linked to transient FAK accumulation at lamellipodia, formation of a FAK–Src-p130Cas–Dock180 signaling complex, elevated Rac and c-Jun NH2-terminal kinase activation, and increased matrix metalloproteinase expression and activity. Our studies support a dual role for FAK in promoting cell motility and invasion through the activation of distinct signaling pathways.

Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) belong to a group of mammalian immunoglobulinrelated glycoproteins. They are involved in cell-cell recognition and modulate cellular processes that range from the shaping of tissue architecture and neovascularization to the regulation of insulin homeostasis and T-cell proliferation. CEACAMs have also been identified as receptors for host-specific viruses and bacteria in mice and humans, respectively, making these proteins an interesting example of pathogen-host co-evolution. Forward and reverse genetics in the mouse now provide powerful novel models to elucidate the action of CEACAM family members in vivo. IntroductionIn multicellular organisms, cell-cell adhesion is vital to guide cells to their proper location during embryonic development and to mediate the integration of single cells into functional tissues and organs. Members of the immunoglobulin superfamily of cell adhesion molecules (IgCAMs) constitute a large group of cell surface glycoproteins with ancient roots in the animal kingdom that specialize in cell-cell adhesion. All IgCAMs posses at least one immunoglobulin (Ig)-like domain, a compact structure $85-110 amino acids long characterized by two b-sheets packed against each other [1]. The Ig fold comes in minor variations that allow subdivision into Ig variable (IgV) and Ig constant (IgC)-1 and -2 domains. In evolutionary terms, the Ig-fold is a success story that has made Ig-domain-encoding sequences the most abundant genes in the human genome. This does not come as a surprise, as the Ig domain seems to be perfectly suited to provide proteins with a universal interface that can be fine-tuned for almost every binding task. In the case of IgCAMs, the binding specificity is often directed towards molecules of their own class or towards themselves, a feature that has been well studied on the genetic, biochemical and structural levels for several neuronal IgCAMs, in particular N-CAM [2,3].Another prominent member of the IgCAM superfamily is the carcinoembryonic antigen (CEA), which is involved in homotypic and heterotypic interactions with other closely related IgCAMs and which constitutes a clinically relevant diagnostic marker in the surveillance of colon tumors. Together with its paralogues, CEA has been grouped in the CEA-related cell adhesion molecule (CEACAM) family, a subdivision of IgCAMs so far only known from mammals [4]. The overall domain organization of human CEACAMs, the number of known splice variants and the distribution of orthologues in other mammalian species is presented in Figure 1. It is important to note that over the years members of the CEACAM family have been going through a number of name changes; for example, the original biliary glycoprotein (Bgp), later classified as the CD66a antigen, has now become CEACAM1 (for current and historic nomenclature of the CEACAM family see also Figure 1). Though CEACAMs have been studied for decades with regard to their tumor-associated features [5], it appears from recent st...