SHC-alpha5beta1 integrin interactions regulate breast cancer cell adhesion and motility.
The oncogenic SHC proteins are signaling substrates for most receptor and cytoplasmic tyrosine kinases (TKs) and have been implicated in cellular growth, transformation, and differentiation. In tumor cells overexpressing TKs, the levels of tyrosine phosphorylated SHC are chronically elevated. The significance of amplified SHC signaling in breast tumorigenesis and metastasis remains unknown. Here we demonstrate that seven- to ninefold overexpression of SHC significantly altered interactions of cells with fibronectin (FN). Specifically, in human breast cancer cells overexpressing SHC (MCF-7/SHC) the association of SHC with alpha5beta1 integrin (FN receptor) was increased, spreading on FN was accelerated, and basal growth on FN was reduced. These effects coincided with an early decline of adhesion-dependent MAP kinase activity. Basal motility of MCF-7/SHC cells on FN was inhibited relative to that in several cell lines with normal SHC levels. However, when EGF or IGF-I was used as the chemoattractant, the locomotion of MCF-7/SHC cells was greatly (approx fivefold) stimulated, while it was only minimally altered in the control cells. These data suggest that SHC is a mediator of the dynamic regulation of cell adhesion and motility on FN in breast cancer cells.
Mauro
L
L
Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania, 19107, USA.
Sisci
D
D
Bartucci
M
M
Salerno
M
M
Kim
J
J
Tam
T
T
Guvakova
M A
MA
Ando
S
S
Surmacz
E
E
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion; D002465:Cell Movement; D005260:Female; D005353:Fibronectins; D006801:Humans; D011506:Proteins / Q000378:metabolism*; D017469:Receptors, Fibronectin / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014407:Tumor Cells, Cultured; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D005353:Fibronectins; D011506:Proteins; D017469:Receptors, Fibronectin; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1