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J Biol Chem, Vol. 274, Issue 44, 31261-31271, October 29, 1999

Cholecystokinin Activates PYK2/CAK by a Phospholipase C-dependent Mechanism and Its Association with the Mitogen-activated Protein Kinase Signaling Pathway in Pancreatic Acinar Cells

Jose A. Tapia, Heather A. Ferris^§, Robert T. Jensen^§, and Luis J. García

From the ^§ Digestive Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 and  Departamento de Fisiología, Universidad de Extremadura, Cáceres 10071, Spain

PYK2/CAK is a recently described cytoplasmic tyrosine kinase related to p125 focal adhesion kinase (p125^FAK) that can be activated by a number of stimuli including growth factors, lipids, and some G protein-coupled receptors. Studies suggest PYK2/CAK may be important for coupling various G protein-coupled receptors to the mitogen-activated protein kinase (MAPK) cascade. The hormone neurotransmitter cholecystokinin (CCK) is known to activate both phospholipase C-dependent cascades and MAPK signaling pathways; however, the relationship between these remain unclear. In rat pancreatic acini, CCK-8 (10 nM) rapidly stimulated tyrosine phosphorylation and activation of PYK2/CAK by both activation of high affinity and low affinity CCK_A receptor states. Blockage of CCK-stimulated increases in protein kinase C activity or CCK-stimulated increases in [Ca²⁺]_i, inhibited by 40-50% PYK2/CAK but not p125^FAK tyrosine phosphorylation. Simultaneous blockage of both phospholipase C cascades inhibited PYK2/CAK tyrosine phosphorylation completely and p125^FAK tyrosine phosphorylation by 50%. CCK-8 stimulated a rapid increase in PYK2/CAK kinase activity assessed by both an in vitro kinase assay and autophosphorylation. Total PYK2/CAK under basal conditions was largely localized (77 ± 7%) in the membrane fraction, whereas total p125^FAK was largely localized (86 ± 3%) in the cytosolic fraction. With CCK stimulation, both p125^FAK and PYK2/CAK translocated to the plasma membrane. Moreover CCK stimulation causes a rapid formation of both PYK2/CAK-Grb2 and PYK2/CAK-Crk complexes. These results demonstrate that PYK2/CAK and p125^FAK are regulated differently by CCK_A receptor stimulation and that PYK2/CAK is probably an important mediator of downstream signals by CCK-8, especially in its ability to activate the MAPK signaling pathway, which possibly mediates CCK growth effects in normal and neoplastic tissues.

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