PMID- 21119598
OWN - NLM
STAT- MEDLINE
DCOM- 20110606
LR  - 20220410
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 30
IP  - 13
DP  - 2011 Mar 31
TI  - Ligand-independent activation of c-Met by fibronectin and alpha(5)beta(1)-integrin 
      regulates ovarian cancer invasion and metastasis.
PG  - 1566-76
LID - 10.1038/onc.2010.532 [doi]
AB  - The role of the fibronectin receptor, alpha(5)beta(1)-integrin, as an adhesion receptor 
      and in angiogenesis is well established. However, its role in cancer cell 
      invasion and metastasis is less clear. We describe a novel mechanism by which 
      fibronectin regulates ovarian cancer cell signaling and promotes metastasis. 
      Fibronectin binding to alpha(5)beta(1)-integrin led to a direct association of 
      alpha(5)-integrin with the receptor tyrosine kinase, c-Met, activating it in a 
      hepatocyte growth factor/scatter factor (HGF/SF) independent manner. 
      Subsequently, c-Met associated with Src, and activated Src and focal adhesion 
      kinase (FAK). Inhibition of alpha(5)beta(1)-integrin decreased the phosphorylation of 
      c-Met, FAK and Src, both in vitro and in vivo. Independent activation of c-Met by 
      its native ligand, HGF/SF, or overexpression of a constitutively active FAK in 
      HeyA8 cells could overcome the effect of alpha(5)beta(1)-integrin inhibition on tumor 
      cell invasion, indicating that alpha(5)beta(1)-integrin is upstream of c-Met, Src and 
      FAK. Inhibition of alpha(5)beta(1)-integrin on cancer cells in two xenograft models of 
      ovarian cancer metastasis resulted in a significant decrease of tumor burden, 
      which was independent of the effect of alpha(5)beta(1)-integrin on angiogenesis. These 
      data suggest that fibronectin promotes ovarian cancer invasion and metastasis 
      through an alpha(5)beta(1)-integrin/c-Met/FAK/Src-dependent signaling pathway, 
      transducing signals through c-Met in an HGF/SF-independent manner.
FAU - Mitra, A K
AU  - Mitra AK
AD  - Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, Center 
      for Integrative Science, University of Chicago, Chicago, IL 60637, USA.
FAU - Sawada, K
AU  - Sawada K
FAU - Tiwari, P
AU  - Tiwari P
FAU - Mui, K
AU  - Mui K
FAU - Gwin, K
AU  - Gwin K
FAU - Lengyel, E
AU  - Lengyel E
LA  - eng
GR  - R01 CA111882/CA/NCI NIH HHS/United States
GR  - R01 CA111882-05/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20101129
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Fibronectins)
RN  - 0 (Integrin alpha5beta1)
RN  - 0 (Ligands)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 2.7.10.2 (Focal Adhesion Kinase 1)
RN  - EC 2.7.10.2 (PTK2 protein, human)
RN  - EC 2.7.10.2 (src-Family Kinases)
SB  - IM
CIN - Cell Adh Migr. 2011 May-Jun;5(3):209-10. PMID: 21436615
MH  - Animals
MH  - Cell Line, Tumor
MH  - Female
MH  - Fibronectins/*physiology
MH  - Focal Adhesion Kinase 1/metabolism
MH  - Humans
MH  - Integrin alpha5beta1/*physiology
MH  - Ligands
MH  - Mice
MH  - Neoplasm Invasiveness
MH  - Neoplasm Metastasis
MH  - Neovascularization, Pathologic/etiology
MH  - Ovarian Neoplasms/blood supply/*pathology
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-met/*physiology
MH  - Signal Transduction
MH  - src-Family Kinases/metabolism
PMC - PMC3069218
MID - NIHMS244406
EDAT- 2010/12/02 06:00
MHDA- 2011/06/07 06:00
PMCR- 2011/09/30
CRDT- 2010/12/02 06:00
PHST- 2010/12/02 06:00 [entrez]
PHST- 2010/12/02 06:00 [pubmed]
PHST- 2011/06/07 06:00 [medline]
PHST- 2011/09/30 00:00 [pmc-release]
AID - onc2010532 [pii]
AID - 10.1038/onc.2010.532 [doi]
PST - ppublish
SO  - Oncogene. 2011 Mar 31;30(13):1566-76. doi: 10.1038/onc.2010.532. Epub 2010 Nov 
      29.