LKB1: cancer, polarity, metabolism, and now fertility

Abstract

The LKB1 serine/threonine kinase is a tumour suppressor responsible for the inherited familial cancer disorder Peutz-Jeghers syndrome and is inactivated in a large percentage of human lung cancers. LKB1 acts a master kinase, directly phosphorylating and activating a family of 14 AMPK (AMP-activated protein kinase)-related kinases which control cell metabolism, cell growth and cell polarity. In this issue of the Biochemical Journal, Hardie and colleagues discover an alternative splice form of LKB1 that alters the C-terminus of the protein containing a few known sites of post-translational regulation. Although widely expressed, the short isoform (LKB1(s)) is the sole splice isoform expressed in testes, and its expression peaks at the time of spermatid maturation. Male mice lacking the LKB1(s) isoform have dramatic defects in spermatozoa, resulting in sterility.

Figure 1

A. Schematic of the two alternative splice forms of LKB1 (numbering according to human LKB1). LKB1l contains exon 9B which includes the well-documented Ser428 phosphorylation site which is a target for PKA and Rsk (and perhaps aPKCs), as well as the Cys430 farnesylation site, both of which are conserved back to Drosophila. B. Both isoforms of LKB1 appear to activate 14 members of the AMPK-related family of kinases, many of which have well-established roles in the control of cell polarity (SAD, MARK subgroups) as well as in cell growth and/or the control of glucose metabolism (AMPK, SIKs). Little is known about the function SnRK or the Ark5/SNARK family and many of these kinases may share overlapping substrates so designating some as regulating cell polarity and others as regulating cell growth/metabolism is somewhat arbitrary.