Integrin β4 regulates SPARC protein to promote invasion.
The α6β4 integrin (referred to as "β4" integrin) is a receptor for laminins that promotes carcinoma invasion through its ability to regulate key signaling pathways and cytoskeletal dynamics. An analysis of published Affymetrix GeneChip data to detect downstream effectors involved in β4-mediated invasion of breast carcinoma cells identified SPARC, or secreted protein acidic and rich in cysteine. This glycoprotein has been shown to play an important role in matrix remodeling and invasion. Our analysis revealed that manipulation of β4 integrin expression and signaling impacted SPARC expression and that SPARC facilitates β4-mediated invasion. Expression of β4 in β4-deficient cells reduced the expression of a specific microRNA (miR-29a) that targets SPARC and impedes invasion. In cells that express endogenous β4, miR-29a expression is low and β4 ligation facilitates the translation of SPARC through a TOR-dependent mechanism. The results obtained in this study demonstrate that β4 can regulate SPARC expression and that SPARC is an effector of β4-mediated invasion. They also highlight a potential role for specific miRNAs in executing the functions of integrins.
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and.
Kristin D
KD
Gerson
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and.
Jeffrey R
JR
Shearstone
High Throughput Genomics, Inc., Tucson, Arizona 85706.
V S R Krishna
VSRK
Maddula
High Throughput Genomics, Inc., Tucson, Arizona 85706.
Bruce E
BE
Seligmann
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and. Electronic address: arthur.mercurio@umassmed.edu.
Arthur M
AM
Mercurio
D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039663:Integrin beta4 / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015676:Osteonectin / Q000096:biosynthesis* / Q000235:genetics; D014176:Protein Biosynthesis
C059834:ITGB4 protein, human; D039663:Integrin beta4; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D015676:Osteonectin