Insulin-like growth factor-binding protein-5-induced laminin gamma1 transcription requires filamin A.
Insulin-like growth factor-binding protein-5 (IGFBP-5) has IGF-1-independent intranuclear effects that are poorly defined. Treatment of cells with IGFBP-5 induces migration, prevents apoptosis, and leads to increased laminin subunit transcription. Similarly, filamin A (FLNa), an actin-binding protein that participates in cell attachment, plays important additional roles in signal transduction and modulation of transcriptional responses. In this report, we show that IGFBP-5 leads to dephosphorylation of FLNa with subsequent FLNa cleavage. Following cleavage, there is enhanced recruitment of Smad3/4 to a C-terminal FLNa fragment with nuclear translocation and subsequent binding to the promoter region of the laminin gamma1 (lamc1) gene. FLNa knockdown prevents IGFBP-5-mediated increases in lamc1 transcription. These data indicate that IGFBP-5 induces formation of a FLNa-based nuclear shuttle that recruits transcription factors and regulates transcription of IGFBP-5 target genes. These studies provide new insights into the mechanisms whereby IGFBP-5 and FLNa exert intranuclear effects.
Abrass
Christine K
CK
Department of Medicine, Allergy & Inflammation Program, University of Washington School of Medicine, Seattle, Washington 98109, USA. cabrass@u.washington.edu
Hansen
Kim M
KM
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003285:Contractile Proteins / Q000378:metabolism*; D064448:Filamins; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism / Q000494:pharmacology*; D007797:Laminin / Q000096:biosynthesis*; D008840:Microfilament Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D017434:Protein Structure, Tertiary; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D051900:Smad3 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology
D003285:Contractile Proteins; D064448:Filamins; D018975:Insulin-Like Growth Factor Binding Protein 5; D007797:Laminin; D008840:Microfilament Proteins; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D051901:Smad4 Protein; C490811:Smad4 protein, rat; C089141:laminin gamma 1