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PMID: 12456636 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth.

The EMBO journal ·Vol. 21 ·No. 23 ·2002-12-02 ·Pages 6289-302

Hauck CR, Hsia DA, Puente XS, Cheresh DA, Schlaepfer DD

Abstract

Focal adhesion kinase (FAK) was first identified as a viral Src (v-Src) substrate, but the role of FAK in Src transformation events remains undefined. We show that stable expression of the FAK C-terminal domain (termed FRNK) in v-Src-transformed NIH 3T3 fibroblasts inhibited cell invasion through Matrigel and blocked experimental metastases in nude mice without effects on cell motility. FRNK inhibitory activity was dependent upon its focal contact localization. FRNK expression disrupted the formation of a v-Src-FAK signaling complex, inhibited p130Cas tyrosine phosphorylation, and attenuated v-Src-stimulated ERK and JNK kinase activation. However, FRNK did not affect v-Src-stimulated Akt activation, cell growth in soft agar, or subcutaneous tumor formation in nude mice. FRNK-expressing cells exhibited decreased matrix metalloproteinase-2 (MMP-2) mRNA levels and MMP-2 secretion. Transient FRNK expression in human 293 cells inhibited exogenous MMP-2 promoter activity and overexpression of wild-type but not catalytically-inactive (Ala-404) MMP-2 rescued v-Src-stimulated Matrigel invasion in the presence of FRNK. Our findings show the importance of FAK in Src-stimulated cell invasion and support a role for Src-FAK signaling associated with elevated tumor cell metastases.

MeSH Terms
3T3 Cells Animals Cell Movement/genetics Lung Neoplasms/genetics,prevention & control,secondary Matrix Metalloproteinase 2/metabolism,physiology Mice Mice, Nude Mitogen-Activated Protein Kinase 1/physiology Mitogen-Activated Protein Kinase 8 Mitogen-Activated Protein Kinases/physiology Oncogene Protein pp60(v-src)/physiology Protein Serine-Threonine Kinases Protein-Tyrosine Kinases/genetics,physiology Proto-Oncogene Proteins/physiology Proto-Oncogene Proteins c-akt Signal Transduction/genetics,physiology
Chemicals
Proto-Oncogene Proteins FAK-related nonkinase Protein-Tyrosine Kinases Oncogene Protein pp60(v-src) Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 8 Mitogen-Activated Protein Kinases Matrix Metalloproteinase 2
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Hauck Christof R
Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Hsia Datsun A
Puente Xose S
Cheresh David A
Schlaepfer David D
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/cdf631
Published
2002-12-02
Pages
6289-302
Language
English
Region
England
NLM ID
8208664
PMCID
PMC136935
Subset
IM
Grants
NCI NIH HHS · R29 CA075240 · United States
NCI NIH HHS · R01 CA087038 · United States
NCI NIH HHS · R37 CA050286 · United States
NCI NIH HHS · CA87038 · United States
NCI NIH HHS · R01 CA050286 · United States
NCI NIH HHS · CA50286 · United States
NCI NIH HHS · CA75240 · United States
NCI NIH HHS · P01 CA078045 · United States
NCI NIH HHS · R01 CA045726 · United States
NCI NIH HHS · R01 CA075240 · United States
NCI NIH HHS · CA78045 · United States
NCI NIH HHS · CA45726 · United States
External Links
PubMed source DOI: 10.1093/emboj/cdf631 PMC Full Text View journal details
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