Breaking the epithelial polarity barrier in cancer: the strange case of LKB1/PAR-4.
The PAR clan of polarity regulating genes was initially discovered in a genetic screen searching for genes involved in asymmetric cell divisions in the Caenorhabditis elegans embryo. Today, investigations in worms, flies and mammals have established PAR proteins as conserved and fundamental regulators of animal cell polarization in a broad range of biological phenomena requiring cellular asymmetries. The human homologue of invertebrate PAR-4, a serine-threonine kinase LKB1/STK11, has caught attention as a gene behind Peutz-Jeghers polyposis syndrome and as a bona fide tumour suppressor gene commonly mutated in sporadic cancer. LKB1 functions as a master regulator of AMP-activated protein kinase (AMPK) and 12 other kinases referred to as the AMPK-related kinases, including four human homologues of PAR-1. The role of LKB1 as part of the energy sensing LKB1-AMPK module has been intensively studied, whereas the polarity function of LKB1, in the context of homoeostasis or cancer, has gained less attention. Here, we focus on the PAR-4 identity of LKB1, discussing the weight of evidence indicating a role for LKB1 in regulation of cell polarity and epithelial integrity across species and highlight recent investigations providing new insight into the old question: does the PAR-4 identity of LKB1 matter in cancer?
Cancer Cell Circuitry Laboratory, Translational Cancer Biology Research Program and Institute of Biomedicine, University of Helsinki, , Biomedicum Helsinki, Rm B507b, PO Box 63, Haartmaninkatu 8, 00014 Helsinki, Finland.
Johanna I
JI
Partanen
Topi A
TA
Tervonen
Juha
J
Klefström
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D016764:Cell Polarity / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D009024:Morphogenesis / Q000502:physiology*; D009369:Neoplasms / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases
LKB1; PAR-4; basement membrane; cancer; cell polarity; hepsin