Elevated glucocorticoid receptor transactivation and down-regulation of alpha(1) integrin are associated with loss of plasma membrane Ca2+-ATPase isoform 1

We have previously shown that inhibition of expression of the plasma membra ne Ca2+-ATPase isoform I in PC6 cells leads to loss of nerve growth factor- mediated neurite extension (Brandt, P, C,, Sisken, J, E,, Neve, R, L,, and Vanaman, T, C, (1996) Proc. Natl, Acad, Sci, U.S.A. 93, 13843-13848). Cells lacking plasma membrane Ca2+-ATPase 1 did not attach to collagen-coated pl ates as tightly as controls, suggesting that a defect in adhesion might be underlying the inability to extend neurites, We report here that cell lines lacking plasma membrane Ca2+-ATPase 1 do not produce alpha(1) integrin, wh ich is required for both collagen adherence and neurite extension. Because alpha(1) integrin gene transcription can be down-regulated by glucocorticoi ds, the response of cells to glucocorticoids was investigated. Cortisol-dep endent transactivation from the mouse mammary tumor virus promoter in cells lacking plasma membrane Ca2+-ATPase 1 was stimulated 145-216-fold over unt reated cells compared with 15-26-fold for controls. This increase was not d ue to increased binding affinity of the receptor for cortisol, an increased number of cortisol-binding sites, or increased translocation of the recept or to the nucleus, Expression of additional glucocorticoid receptor-depende nt genes required for neurite extension must also be altered in cells missi ng the plasma membrane Ca2+-ATPase 1 because constitutive expression of alp ha(1) integrin did not restore their nerve growth factor-mediated neurite e xtension capability. The impact of plasma membrane Ca2+-ATPase isoform 1 on other signaling systems and the resultant profound yet subtle effects on P C6 cells strongly suggests that it plays an important role in modulating si gnal transduction pathways downstream of Ca2+-mediated signals.