title: HLJ1 is an endogenous Src inhibitor suppressing cancer progression through dual mechanisms.
abstract: HLJ1 (DNAJB4), a DNAJ/Hsp40 chaperone, has emerged as a novel prognostic marker in lung cancers; however, the molecular contribution and functionality in neoplastic diseases remain to be established. This study demonstrated that HLJ1 inhibits epithelial-mesenchymal transition in vitro and reduces lung cancer metastasis in vivo. Using shRNA silencing and ectopic expression of HLJ1, we found that HLJ1 not only suppresses catalytic activity of Src but also downregulates the formation of oncogenic complexes associated with the EGFR, FAK and STAT3 signaling pathways. A screen of specimens from HLJ1-knockout mice and lung cancer patients validated that HLJ1 expression is inversely correlated with Src activity. Mechanistically, HLJ1 protein directly bound to catalytic and protein-binding domains of Src through its amino acid Y172 and the P301/P304 motif. Following Src-induced HLJ1 phosphorylation at Y172, HLJ1-Src interaction was elevated, resulting in Src inhibition and malignancy suppression. Interestingly, both Src-binding regions also occurred in other DNAJB family members and contributed to anti-invasive activities of DNAJB proteins. We conclude that HLJ1 is an endogenous Src inhibitor that can suppress cancer metastasis through complex interacting mechanisms. This HLJ1-Src complex might provide a promising molecular model for developing new anticancer strategies.
authors.affiliation: Department of Internal Medicine and Center for Comparative Respiratory Biology and Medicine, University of California Davis, Davis, CA, USA.|Division of Nephrology, Department of Internal Medicine, University of California Davis, Davis, CA, USA.
authors.forename: C-H
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: W-H
authors.initials: WH
authors.lastname: Chang
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan.|Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: K-Y
authors.initials: KY
authors.lastname: Su
authors.affiliation: Taipei Institute of Pathology, Taipei, Taiwan.
authors.forename: W-H
authors.initials: WH
authors.lastname: Ku
authors.affiliation: Division of Chest Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: G-C
authors.initials: GC
authors.lastname: Chang
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Q-S
authors.initials: QS
authors.lastname: Hong
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Hsiao
authors.affiliation: Department of Life Science, National Chung Hsing University, Taichung, Taiwan.
authors.forename: H-C
authors.initials: HC
authors.lastname: Chen
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine and Center for Comparative Respiratory Biology and Medicine, University of California Davis, Davis, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Wu
authors.affiliation: Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: P-C
authors.initials: PC
authors.lastname: Yang
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.|Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan.
authors.forename: J J W
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan.|Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Center for Optoelectronic Biomedicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: S-L
authors.initials: SL
authors.lastname: Yu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D050956:HSP40 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018909:src Homology Domains; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: C494650:DNAJB4 protein, human; D050956:HSP40 Heat-Shock Proteins; D034741:RNA, Small Interfering; D019061:src-Family Kinases