CELLULAR BASIS OF ACTION OF GASTROINTESTINAL PEPTIDES

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Bombesin- and CCK-related peptides are found widely in the gastrointestinal (GI) tract and central nervous system, however, aspects of their cellular basis of action remain unclear, particularly the role of tyrosine phosphorylation in their signaling cascade. In our recent studies the cellular basis of action of bombesin receptors and cholecystokinin-A (CCK) receptors [CCK-A-R] are being examined. A new bombesin receptor that has been described in amphibians, bombesin receptor subtype-4 [BB-4-R] and during this last year it has been successfully stably expressed in a mammalian cell, CHO-K-1 which allows its cell biology and pharmacology to be studied for the first time. Our studies demonstrate this receptor is coupled to phospholipase C with activation stimulating both changes in (Ca-2+),-and inositol phosphates, as well as being coupled to phospholipase D [Biochemistry 38:7307, 1999.] In previous studies CCK-A-R activation has been shown to be coupled to activation of phospholipase C with mobilization of cellular [Ca-2+], and activation of PKC, PLD, and PLA-2. Recent studies by us (Adv. Mol. Cell. Endrinol. 3, 119, 1999) and others show increased tyrosine phosphorylation may also be an important cellular cascade. We have demonstrated CCK-A-R causes tyrosine phosphorylation of p125 focal adhesion kinase and paxillin and in a study this year demonstrated it also caused tyrosine phosphorylation of p130-cas (Biochemistry 38:1497, 1999). We found rapid tyrosine phosphorylation of p130-cas (Crk-associated substrate) by CCK through PLC dependent-and independent pathways that was dependent on the small G protein, p21-rho and the integrity of the actin cytoskeleton. Activation of this pathway resulted in the translocation of p130-cas to the plasma membrane and coupling to c-CrK. Because p130-cas is a major intracellular adapter molecule with both numerous SH-3 and SH-2 binding domains, as is CrK, and functions as a molecular switch, its activation suggests it may be an important mediator of CCKs downstream effects, especially growth. - bombesin receptors, CCK receptors, p125-FAK, p130-cas,