In the past decade, research on the human tumor suppressor LKB1 has uncovered a novel signaling pathway linking cell metabolism to growth control and cell polarity. LKB1 encodes a serine/threonine kinase that directly phosphorylates and activates AMPK, a central metabolic sensor. AMPK regulates lipid, cholesterol and glucose metabolism in specialized metabolic tissues such as liver, muscle and fat, which makes it a key therapeutic target for patients with diabetes. The association of AMPK with several tumor suppressors suggests that established therapeutics for this pathway in diabetic drugs deserve further study in cancer patients.
Figure 1. Protein structure of LKB.
LKB1 is a master kinase
Finding LKB1 substrates that mediate its tumor suppressor function led to the identification of AMPK as a direct substrate 1-4. AMPK is a heterotrimer composed of the catalytic (AMPKα subunit and two regulatory AMKPβ and AMPKγ) subunits (Figure 2). When intracellular ATP decreases and intracellular AMP increases, such as when nutrition is deficient or hypoxia, AMPK is activated. Studies in worms, fruit flies, and mice have shown that LKB1 is the major kinase 9 that phosphorylates the AMPKα activation loop under energy stress conditions.
LKB1 also phosphorylates and activates 12 kinases closely related to AMPK10 11 (Figure 3). Of these 14 kinases, most recent data indicate that only AMPKα1 and AMPKα2 are activated under low ATP conditions, probably because they only interact with AMPKγ12. Interestingly, four of these 14 kinases are mammalian members of the MAP/microtubule affinity-regulated kinase (MARK)/Par-1 family, which are mammalian homologues of C. elegans par-1 kinase, Required for early embryo distribution and polarity. Par-4 encodes the C. elegans ortholog of LKB113. The ability of LKB1 (or its orthologs) to act as an upstream upstream kinase that activates AMPK, MARK/par-1, and several other AMPK-related kinases appears to be widely conserved throughout eukaryotes.
A LKB1-AMPK-mTORC1 checkpoint
Before being identified as a substrate for LKB1, AMPK was known to regulate lipid, cholesterol, and glucose metabolism in specialized metabolic tissues such as liver, muscle, and fat. Studies from multiple laboratories over the past 5 years have shown that one of the major growth-regulating pathways controlled by LKB1-AMPK is the mammalian rapamycin target (mTOR) pathway. mTOR is a major integrator of nutrient and growth factor inputs that controls the growth of all eukaryotic cells and is loosely regulated in most human cancers. mTOR exists in two biochemical and functionally discrete signal complexes. The mTOR complex 1 (mTORC1) includes raptors that serve as scaffolds to recruit downstream substrates such as EBP1 and ribosomal S6 kinase (p70S6K1), which help regulate mTORC1-dependent protein translation. mTORC1 controls the translation of many cell growth regulators, including cyclin D1, hypoxia-inducible factor 1a (HIF-1α and c-myc), which in turn promotes cell cycle progression, cell growth, and angiogenesis. All of this can be turned into. Although recent studies show that rapamycin cannot completely inhibit mTORC1 activity in many cell types, mTORC1 is sensitive to nutrition and acutely inhibited by rapamycin.
Expression
Testosterone and DHT treated mice with 3T3-L1 or human SGBS adipocytes for 24 hours can significantly reduce LKB1 mRNA expression via the androgen receptor, thereby reducing the activation of AMPK by phosphorylation. In contrast, 17β-estradiol treatment increased LKB1 mRNA (estrogen receptor alpha-mediated effects). However, in ER-positive breast cancer cell MCF-7, estradiol caused a dose-dependent decrease in LKB1 transcript and protein expression, which resulted in a significant increase in the level of phosphorylation of LKB1 target AMPK. ERα binds to the STK11 promoter in a ligand-independent manner, and this interaction is reduced in the presence of estradiol. In addition, STK11 promoter activity was significantly reduced in the presence of estradiol.
Clinical significance
Germline mutations in this gene are associated with Peutz-Jeghers syndrome, an autosomal dominant genetic disease that is characterized by the growth of gastrointestinal polyps, skin and oral pigmentation, and other tumors. However, the LKB1 gene has also been found to be mutated in sporadic lung cancer, mainly adenocarcinoma. In addition, recent studies have found a large number of somatic mutations in the LKB1 gene in cervical, breast, bowel, testicular, pancreatic and skin cancers.
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