Primary keratinocytes were isolated from neonatal human foreskins as described previously (21).

These results suggest that JNK may be a novel regulator of cell-cell adhesion and may have wide implications in understanding important biological processes, such as tissue development, tissue regeneration, and cancer metastasis. Here, we show that JNK binds to and phosphorylates β-catenin and regulates formation of adherens junctions. On the other hand, serine phosphorylated β-catenin can be incorporated in newly formed adherens junctions but undergoes dephosphorylation as junctions mature (20). Phosphorylation of the cytoplasmic domain of E-cadherin results in enhanced cell adhesion (18), whereas tyrosine phosphorylation of β-catenin has been implicated in adherens junction disassembly (19). The C terminus of β-catenin interacts with E-cadherin, whereas its N-terminal portion interacts with α-catenin, which is directly responsible for linking adherens junctions to the actin cytoskeleton (17). The cytoplasmic domain of E-cadherin forms complexes with plaque proteins known as catenins, namely α-catenin and β-catenin.

In epithelial cells, adherens junctions are formed by calcium-dependent homotypic interactions between E-cadherins on the surface of opposing cells. Furthermore, a pool of phosphorylated JNK is localized in focal adhesions (14), where it promotes cell migration by phosphorylating the focal adhesion protein paxillin (15).Ĭell-cell adhesion is crucial to many aspects of multicellular existence, including morphogenesis, tissue integrity, and differentiation (16). In mammalian cells, JNK is phosphorylated only in cells at the edge of the wound, and inhibition of JNK pathway blocks migration and lamellipodia extension (13). Subsequent studies suggested that JNK signaling may also be important in movement of epithelial sheets (5, 6), wound healing (7), apoptosis (8, 9, 10), cell survival (11), and tumor development (12).

JNKs were originally identified by their ability to phosphorylate c-jun in response to stress induced by a variety of stimuli, such as TNF-α (3) or UV radiation (4). The c-Jun N-terminal kinases (JNKs), also known as stress-activated protein kinases, belong to the mitogen-activated protein kinase (MAPK) group of serine threonine protein kinases (1, 2).

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