title: Phosphorylation of LCRMP-1 by GSK3β promotes filopoda formation, migration and invasion abilities in lung cancer cells.
abstract: LCRMP-1, a novel isoform of CRMP-1, can promote cancer cell migration, invasion and associate with poor clinical outcome in patients with non-small-cell lung cancer (NSCLC). However, the underlying regulatory mechanisms of LCRMP-1 in cancer cell invasiveness still remain obscure. Here, we report that GSK3β can phosphorylate LCRMP-1 at Thr-628 in consensus sequences and this phosphorylation is crucial for function of LCRMP-1 to promote filopodia formation, migration and invasion in cancer cells. Impediment of Thr-628 phosphorylation attenuates the stimulatory effects of LCRMP-1 on filopodia forming, migration and invasion abilities in cancer cells; simultaneously, kinase-dead GSK3β diminishes regulation of LCRMP-1 on cancer cell invasion. Furthermore, we also found that patients with low-level Ser-9-phosphorylated GSK3β expression and high-level LCRMP-1 expression have worse overall survival than those with high-level inactive GSK3β expressions and low-level LCRMP-1 expressions (P<0.0001). Collectively, these results demonstrate that GSK3β-dependent phosphorylation of LCRMP-1 provides an important mechanism for regulation of LCRMP-1 on cancer cell invasiveness and clinical outcome.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Wen-Lung
authors.initials: WL
authors.lastname: Wang
authors.forename: Tse-Ming
authors.initials: TM
authors.lastname: Hong
authors.forename: Yih-Leong
authors.initials: YL
authors.lastname: Chang
authors.forename: Chen-Tu
authors.initials: CT
authors.lastname: Wu
authors.forename: Szu-Hua
authors.initials: SH
authors.lastname: Pan
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
mesh_terms: D000595:Amino Acid Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D016016:Proportional Hazards Models; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011554:Pseudopodia / Q000378:metabolism*; D013379:Substrate Specificity; D000098855:Collapsin Response Mediator Protein 1
chemical_list: D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D009419:Nerve Tissue Proteins; D010769:Phosphothreonine; D020033:Protein Isoforms; C102924:CRMP1 protein, human; D000098855:Collapsin Response Mediator Protein 1; C000605506:GSK3B protein, human