Tumor suppression by LKB1: SIK-ness prevents metastasis.
The LKB1 serine-threonine kinase is a tumor suppressor that is inactivated in a large number of sporadic human lung non-small cell carcinomas (NSCLCs) and cervical cancers. Genetic deletion of LKB1 in various mouse tissues results in tumorigenesis, and loss of LKB1 increases metastasis in a mouse model of NSCLC. LKB1 directly activates a family of 14 kinases related to AMPK [adenosine monophosphate (AMP)-activated protein kinase] to control cell metabolism, growth, and polarity, though which of these are critical to its tumor suppressor functions remain undefined. The LKB1-dependent kinase SIK1 (salt-inducible kinase 1) has now been identified as a key modulator of anoikis (apoptosis induced by cell detachment) and transformation in culture, and its modulation of the tumor suppressor p53 controls metastasis in transplanted tumor cells. Reduced SIK1 expression is correlated with poor prognosis in two large human breast cancer data sets. These findings suggest that SIK1 is a key upstream regulator of p53-dependent anoikis that may be targeted in tumorigenesis.
Shaw
Reuben J
RJ
Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. shaw@salk.edu
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19; D004789:Enzyme Activation; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010580:Peutz-Jeghers Syndrome / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000627:therapeutic use*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000473:pathology
D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases