The STK11 protein is mainly comprised of three major domains: an N-terminal non-catalytic domain that contains the nuclear localization signal, a catalytic kinase domain that is important for ATP binding, and a C-terminal non-catalytic regulatory domain that contains a prenylation motif (CAAX-box) [10
]. Codons 49-309 encode the catalytic kinase domain. The C-terminal non-catalytic region of the STK11 protein is encoded by exon 8 and 9, and encompasses amino acids 309-433. In these two Chinese families, the mutation, c.904C > T (p.Q302X), results in the premature termination of the 433 amino acid protein at codon 302, which leads to partial loss of the kinase domain and complete loss of the C-terminal regulatory domain (CRD). With this mutation, patient II:6 in family 1 developed colon adenocarcinoma at 60 years of age and died one year later, and patient II:2 in family 2 died from liver cancer at 45 years of age. These findings suggest that the novel mutation, p.Q302X, is most likely responsible for the development of the PJS phenotype and may even contribute to malignancy.
Although the exact function of STK11 remains largely unknown, studies suggest that it plays a role in cell signaling and apoptosis [11
]. Development of the PJS phenotypes is believed to be due to the elimination of the kinase activity of STK11, which is associated with a loss of growth suppression function [12
]. Recently, several proteins, including p53, Cdc37, Hsp90, and PTEN, which are responsible for cancer syndromes when mutated or involved in cancer pathways, were reported to interact with the kinase domain of STK11; however, the protein interaction domains have not been mapped [13
]. Accordingly, the interaction domain for one of these proteins may be localized to codon 302, and therefore could explain the high cancer risk of mutations within this site. Moreover, the C-terminal domain of STK11 is important for binding STRAD, which is a protein that is possibly involved in MAPK signaling, control of the AMPK pathway (a key regulator of cellular metabolism), and control of cell polarity [14
]. Taken together, these data suggest that the novel STK11 mutation, c.904C > T (p.Q302X), which was found in two unrelated Chinese PJS families, causes partial loss of the kinase domain and complete loss of the C-terminal domain, and may contribute to polyp formation and tumorgenesis through various mechanisms, such as loss of growth arrest, apoptosis, and loss of cell polarity. Additional studies are needed to address these questions.
A genotype-phenotype correlation has been sought in PJS. Schumacher et al.
] suggested that in-frame mutations in the domains that encode the protein and ATP binding and catalysis (I-VIA) are rarely associated with cancer. Moreover, missense mutations in the C-terminus and in the domains for substrate recognition (VIB-VIII) seem to be more associated with malignancies, and patients with breast carcinomas predominantly had truncating mutations. Mehenni et al.
] suggested that there was a higher risk of cancer in cases with mutations in exon 6 of the STK11 gene. In a large analysis of 240 PJS patients with STK11 mutations, no difference was observed between individuals with missense and truncating mutations or between familial and sporadic cases, although it was suggested that there was a higher risk of cancer in individuals with mutations in exon 3 of the gene. Hearle et al.
] extended this study by analyzing a total of 419 PJS patients, of whom 297 had documented mutations. In that study, it was found that the type and site of mutation did not influence cancer risk.