Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser(431) by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell growth

Peutz-Jeghers syndrome is an inherited cancer syndrome that results in a gr eatly increased risk of developing tumors in those affected, The causative gene is a protein kinase termed LKB1, predicted to function as a tumor supp ressor, The mechanism by which LKB1 is regulated in cells is not known. Her e, we demonstrate that stimulation of Rat-a or embryonic stem cells with ac tivators of ERK1/2 or of cAMP-dependent protein kinase induced phosphorylat ion of endogenously expressed LKB1 at Ser(431), We present pharmacological and genetic evidence that p90(RSK) mediated this phosphorylation in respons e to agonists that activate ERK1/2 and that cAMP-dependent protein kinase m ediated this phosphorylation in response to agonists that activate adenylat e cyclase, Ser(431) of LKB1 lies adjacent to a putative prenylation motif, and we demonstrate that full-length LKB1 expressed in 293 cells was prenyla ted by addition of a farnesyl group to Cys(433). Our data suggest that phos phorylation of LKB1 at Ser(431) does not affect farnesylation and that farn esylation does not affect phosphorylation at Ser(431), Phosphorylation of L KB1 at Ser(431) did not alter the activity of LKB1 to phosphorylate itself or the tumor suppressor protein p53 or alter the amount of LKB1 associated with cell membranes. The reintroduction of wild-type LKB1 into a cancer cel l line that lacks LKB1 suppressed growth, but mutants of LKB1 in which Ser( 431) was mutated to Ala to prevent phosphorylation of LKB1 were ineffective in inhibiting growth. In contrast, a mutant of LKB1 that cannot be prenyla ted was still able to suppress the growth of cells.