HEF1 is a necessary and specific downstream effector
of FAK that promotes the migration of glioblastoma
cells.
Natarajan
M, Stewart JE, Golemis
EA, Pugacheva
EN, Alexandropoulos K,
Cox BD, Wang W, Grammer
JR, Gladson
CL.
1Department of Pathology, Division of Neuropathology,
The highly invasive behavior of glioblastoma cells
contributes to the morbidity and mortality associated with these tumors. The integrin-mediated adhesion and migration of glioblastoma cells on brain matrix proteins is enhanced by
stimulation with growth factors, including platelet-derived growth factor
(PDGF). As focal adhesion kinase (FAK), a nonreceptor cytoplasmic tyrosine kinase, has been shown to promote cell migration in various
other cell types, we analysed its role in glioblastoma cell migration. Forced overexpression
of FAK in serum-starved glioblastoma cells plated on
recombinant (rec)-osteopontin
resulted in a twofold enhancement of basal migration and a ninefold
enhancement of PDGF-BB-stimulated migration. Both expression of mutant FAK(397F) and the downregulation
of FAK with small interfering (si) RNA inhibited
basal and PDGF-stimulated migration. FAK overexpression
and PDGF stimulation was found to increase the phosphorylation
of the Crk-associated substrate (CAS) family member
human enhancer of filamentation 1 (HEF1), but not
p130CAS or Src-interacting protein (Sin)/Efs, although the levels of expression of these proteins
was similar. Moreover downregulation of HEF1 with siRNA, but not p130CAS, inhibited basal and PDGF-stimulated
migration. The phosphorylated HEF1 colocalized with vinculin and was
associated almost exclusively with 0.1% Triton X-100 insoluble material,
consistent with its signaling at focal adhesions. FAK overexpression
promoted invasion through normal brain homogenate and siHEF1 inhibited this
invasion. Results presented here suggest that HEF1 acts as a necessary and
specific downstream effector of FAK in the invasive
behavior of glioblastoma cells and may be an
effective target for treatment of these tumors.Oncogene
advance online publication, 14 November 2005; doi:10.1038/sj.onc.1209199.
PMID: 16288224 [PubMed - as supplied by publisher]