title: Integrin-binding protein nischarin interacts with tumor suppressor liver kinase B1 (LKB1) to regulate cell migration of breast epithelial cells.
abstract: Biallelic inactivation of LKB1, a serine/threonine kinase, has been detected in 30% of lung adenocarcinomas, and inhibition of breast tumor growth has been demonstrated. We have identified the tumor suppressor, Nischarin, as a novel binding partner of LKB1. Our mapping analysis shows that the N terminus of Nischarin interacts with amino acids 44-436 of LKB1. Time lapse microscopy and Transwell migration data show that the absence of both Nischarin and LKB1 from an invasive breast cancer cell line (MDA-MB-231) enhances migration as measured by increased distance and speed of migrating cells. Our data suggest that this is a result of elevated PAK1 and LIMK1 phosphorylation. Moreover, the absence of Nischarin and LKB1 increased tumor growth in vivo. Consistent with this, the percentage of S phase cells was increased, as demonstrated by flow cytometry and enhanced cyclin D1. The absence of Nischarin and LKB1 also led to a dramatic increase in the formation of lung metastases. Our studies, for the first time, demonstrate functional interaction between LKB1 and Nischarin to inhibit cell migration and breast tumor progression. Mechanistically, we show that these two proteins together regulate PAK-LIMK-Cofilin and cyclin D1/CDK4 pathways.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Louisiana State University Health Science Center, New Orleans, Louisiana 70112, USA.
authors.forename: Prachi
authors.initials: P
authors.lastname: Jain
authors.forename: Somesh
authors.initials: S
authors.lastname: Baranwal
authors.forename: Shengli
authors.initials: S
authors.lastname: Dong
authors.forename: Amanda P
authors.initials: AP
authors.lastname: Struckhoff
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Worthylake
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Alahari
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D054755:Imidazoline Receptors / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D054461:Lim Kinases / Q000235:genetics / Q000378:metabolism; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C530104:CCND1 protein, human; D054755:Imidazoline Receptors; D047908:Intracellular Signaling Peptides and Proteins; C458505:NISCH protein, human; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; C515892:LIMK1 protein, human; D054461:Lim Kinases; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D000091162:AMP-Activated Protein Kinase Kinases
keywords: Breast Cancer; Migration; Protein Phosphorylation; Rho GTPases; Tumor Metastases