MULTIPLE SIGNALING PATHWAYS FOR THE ACTIVATION OF JNK IN MAST-CELLS -INVOLVEMENT OF BRUTONS TYROSINE KINASE, PROTEIN-KINASE-C, AND JNK KINASES, SEK1 AND MKK7

Stimulation of the high affinity IgE receptor (Fc epsilon RI) as well as a variety of stresses induce activation of c-Jun N-terminal protein kinases (JNKs) stress-activated protein kinases in mast cells. At lea st three distinct signaling pathways leading to JNK activation have be en delineated based on the involvements of Bruton's tyrosine kinase (B tk), protein kinase C (PKC), and the JNK-activating cascades composed of multiple protein kinases, The PKC-dependent pathway, which is inhib ited by a PKC inhibitor Ro31-8425 and can be activated by PMA, functio ns as a major route in Fc epsilon RI-stimulated mast cells derived fro m btk gene knockout mice. On the other hand, wild-type mouse-derived m ast cells use both PKC-dependent and PKC-independent pathways for JNK activation. A PKC-independent pathway is regulated by Btk and SEK1 via the PAK-->MEKK1-->SEK1-->JNK cascade, and is sensitive to phosphatidy linositol 3-kinase inhibitors, wortmannin and LY-294002, while the PKC -dependent pathway is affected to a lesser extent by both wortmannin t reatment and overexpression of wild-type and dominant negative mutant SEK1 proteins. Another PKC-independent pathway involves Btk and MKK7, a recently cloned direct activator of JNK. Among the stresses tested, UV irradiation seems to activate Btk and JNK via the PKC-independent p athways.