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J. Biol. Chem., Vol. 276, Issue 22, 19469-19482, June 1, 2001

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Phosphorylation of the Protein Kinase Mutated in Peutz-Jeghers Cancer Syndrome, LKB1/STK11, at Ser⁴³¹ by p90^RSK and cAMP-dependent Protein Kinase, but Not Its Farnesylation at Cys⁴³³, Is Essential for LKB1 to Suppress Cell Growth^*

Gopal P. Sapkota^§, Agnieszka Kieloch, Jose M. Lizcano, Sonia Lain^¶, J. Simon C. Arthur, Michayla R. Williams, Nick Morrice, Maria Deak, and Dario R. Alessi

From the  Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland and the ^¶ Cancer Research Campaign Cell Transformation Group, Ninewells Hospital, Dundee DD1 9SY, Scotland

Peutz-Jeghers syndrome is an inherited cancer syndrome that results in a greatly increased risk of developing tumors in those affected. The causative gene is a protein kinase termed LKB1, predicted to function as a tumor suppressor. The mechanism by which LKB1 is regulated in cells is not known. Here, we demonstrate that stimulation of Rat-2 or embryonic stem cells with activators of ERK1/2 or of cAMP-dependent protein kinase induced phosphorylation of endogenously expressed LKB1 at Ser⁴³¹. We present pharmacological and genetic evidence that p90^RSK mediated this phosphorylation in response to agonists that activate ERK1/2 and that cAMP-dependent protein kinase mediated this phosphorylation in response to agonists that activate adenylate cyclase. Ser⁴³¹ of LKB1 lies adjacent to a putative prenylation motif, and we demonstrate that full-length LKB1 expressed in 293 cells was prenylated by addition of a farnesyl group to Cys⁴³³. Our data suggest that phosphorylation of LKB1 at Ser⁴³¹ does not affect farnesylation and that farnesylation does not affect phosphorylation at Ser⁴³¹. Phosphorylation of LKB1 at Ser⁴³¹ 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 cell line that lacks LKB1 suppressed growth, but mutants of LKB1 in which Ser⁴³¹ was mutated to Ala to prevent phosphorylation of LKB1 were ineffective in inhibiting growth. In contrast, a mutant of LKB1 that cannot be prenylated was still able to suppress the growth of cells.

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