GRIM-19 inhibits v-Src-induced cell motility by interfering with cytoskeletal restructuring.
GRIM-19 (Gene associated with Retinoid-Interferon-induced Mortality 19) is a novel tumor suppressor regulated by interferon/retinoid combination. We have recently shown that GRIM-19 inhibits v-Src-induced oncogenic transformation and metastatic behavior of cells. Oncogenic v-Src induces cell motility by cytoskeletal remodeling, especially the formation of podosomes and. Here, we show that GRIM-19 inhibited the v-Src-induced cell motility by inhibiting cytoskeletal remodeling, that is, podosome formation. We also show that the N terminus of GRIM-19 played a major role in this process and identified critical residues in this region. More importantly, we show that tumor-associated GRIM-19 mutations disrupted its ability to inhibit v-Src-induced cell motility. These actions appear to occur independently of STAT3, a known target of GRIM-19-mediated inhibition. Lastly, tumor-associated GRIM-19 mutants significantly lost their ability to control v-Src-induced metastases in vivo, indicating the biological and pathological significance of these observations.
Sun
P
P
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Nallar
S C
SC
Kalakonda
S
S
Lindner
D J
DJ
Martin
S S
SS
Kalvakolanu
D V
DV
D000818:Animals; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D051356:Cortactin / Q000378:metabolism; D003599:Cytoskeleton / Q000737:chemistry*; D051379:Mice; D009247:NADH, NADPH Oxidoreductases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015688:Oncogene Protein pp60(v-src) / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D013329:Structure-Activity Relationship
D051356:Cortactin; D009247:NADH, NADPH Oxidoreductases; C486684:Grim19 protein, mouse; D015688:Oncogene Protein pp60(v-src)