A second protein-tyrosine kinase (PTK) of the focal adhesion kinase (FAK) subfamily, cell adhesion kinase ␤ (CAK␤), was identified by cDNA cloning. The rat CAK␤ is a 115.7-kDa PTK that contains N-and C-terminal domains of 418 and 330 amino acid residues besides the central kinase domain. The rat CAK␤ has a homology with mouse FAK over their entire lengths except for the extreme N-terminal 88 residues and shares 45% overall sequence identity (60% identical in the catalytic domain), which indicates that CAK␤ is a protein structurally related to but different from FAK. The CAK␤ gene is less evenly expressed in a variety of rat organs than the FAK gene. Anti-CAK␤ antibody immunoprecipitated a 113-kDa protein from rat brain, 3Y1 fibroblasts, and COS-7 cells transfected with CAK␤ cDNA. The tyrosinephosphorylated state of CAK␤ was not reduced on trypsinization, nor enhanced in response to plating 3Y1 cells onto fibronectin. CAK␤ localized to sites of cell-tocell contact in COS-7 transfected with CAK␤ cDNA, in which FAK was found at the bottom of the cells. Thus, CAK␤ is a PTK possibly participating in the signal transduction regulated by cell-to-cell contacts. Protein-tyrosine kinases (PTKs)1 that do not span the plasma membranes (so-called nonreceptor PTKs) have been classified into different subclasses (subfamilies) based on the sequence similarity and distinct structural characteristics (1). Many nonreceptor PTKs participate in cellular signal transduction by associating with the intracellular portions of transmembrane receptors which do not themselves have PTK activity. Different nonreceptor PTKs play diverse and specific roles in mediating the signal transduction by different nonkinase receptors (2-4).Focal adhesion kinase (FAK) has been proposed as the prototype (and hitherto the sole member) of a new subfamily of nonreceptor PTK, represented by proteins with large N-and C-terminal domains flanking the catalytic domain but without Src homology 2 and 3 (SH-2 and SH-3) domains (5-9). FAK is concentrated in focal adhesions (5, 6), and its phosphorylation and activation are triggered by the ligand binding to integrins and by the stimulation of certain growth factor and neuropeptide receptors (6, 10 -24). The N-and C-terminal domains of FAK mediate its interactions with integrins, the Src-family kinases and paxillin, a focal adhesion associated protein (8,9,(25)(26)(27)(28). By these and other yet to be characterized interactions, FAK regulates signaling via different receptors. Because only one member of the FAK subfamily is known to date, we sought to identify a second PTK of the FAK subfamily by a homologybased cDNA cloning strategy. We describe here an isolation and characterization of a cDNA coding for a new member of the FAK family. The novel PTK described here is the second member, to our knowledge, of the FAK subfamily whose cDNA has been cloned and sequenced and is designated CAK␤ for cell adhesion kinase ␤.

Tight junctions are intercellular junctions adjacent to the apical end of the lateral membrane surface. They have two functions, the barrier (or gate) function and the fence function. The barrier function of tight junctions regulates the passage of ions, water, and various macromolecules, even of cancer cells, through paracellular spaces. The barrier function is thus relevant to edema, jaundice, diarrhea, and blood-borne metastasis. On the other hand, the fence function maintains cell polarity. In other words, tight junctions work as a fence to prevent intermixing of molecules in the apical membrane with those in the lateral membrane. This function is deeply involved in cancer cell biology, in terms of loss of cell polarity. Of the proteins comprising tight junctions, integral membrane proteins occludin, claudins, and JAMs have been recently discovered. Of these molecules, claudins are exclusively responsible for the formation of tight-junction strands and are connected with the actin cytoskeleton mediated by ZO-1. Thus, both functions of tight junctions are dependent on the integrity of the actin cytoskeleton as well as ATP. Mutations in the claudin14 and the claudin16 genes result in hereditary deafness and hereditary hypomagnesemia, respectively. Some pathogenic bacteria and viruses target and affect the tight-junction function, leading to diseases. In this review, the relationship between tight junctions and human diseases is summarized.

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