title: Liver kinase B1 expression promotes phosphatase activity and abrogation of receptor tyrosine kinase phosphorylation in human cancer cells.
abstract: Aberrant receptor tyrosine kinase phosphorylation (pRTK) has been associated with diverse pathological conditions, including human neoplasms. In lung cancer, frequent liver kinase B1 (LKB1) mutations correlate with tumor progression, but potential links with pRTK remain unknown. Heightened and sustained receptor activation was demonstrated by LKB1-deficient A549 (lung) and HeLaS3 (cervical) cancer cell lines. Depletion (siRNA) of endogenous LKB1 expression in H1792 lung cancer cells also correlated with increased pRTK. However, ectopic LKB1 expression in A549 and HeLaS3 cell lines, as well as H1975 activating-EGF receptor mutant lung cancer cell resulted in dephosphorylation of several tumor-enhancing RTKs, including EGF receptor, ErbB2, hepatocyte growth factor receptor (c-Met), EphA2, rearranged during transfection (RET), and insulin-like growth factor I receptor. Receptor abrogation correlated with attenuation of phospho-Akt and increased apoptosis. Global phosphatase inhibition by orthovanadate or depletion of protein tyrosine phosphatases (PTPs) resulted in the recovery of receptor phosphorylation. Specifically, the activity of SHP-2, PTP-1β, and PTP-PEST was enhanced by LKB1-expressing cells. Our findings provide novel insight on how LKB1 loss of expression or function promotes aberrant RTK signaling and rapid growth of cancer cells.
authors.affiliation: From the Section of Molecular Medicine, and.
authors.forename: Imoh S
authors.initials: IS
authors.lastname: Okon
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Coughlan
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zou
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D014638:Vanadates / Q000494:pharmacology
chemical_list: D014638:Vanadates; D020794:Receptor Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D017027:Protein Tyrosine Phosphatases
keywords: Epidermal Growth Factor Receptor (EGFR); Growth Factors; LKB; LKB1; Lung Cancer; Receptor Tyrosine Kinase