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PMID: 11359909 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Epidermal growth factor-induced tumor cell invasion and metastasis initiated by dephosphorylation and downregulation of focal adhesion kinase.

Molecular and cellular biology ·Vol. 21 ·No. 12 ·2001-06-00 ·Pages 4016-31

Lu Z, Jiang G, Blume-Jensen P, Hunter T

Abstract

Upregulated epidermal growth factor (EGF) receptor (EGFR) expression and EGFR-induced signaling have been correlated with progression to invasion and metastasis in a wide variety of carcinomas, but the mechanism behind this is not well understood. We show here that, in various human carcinoma cells that overexpress EGFR, EGF treatment induced rapid tyrosine dephosphorylation of focal adhesion kinase (FAK) associated with downregulation of its kinase activity. The downregulation of FAK activity was both required and sufficient for EGF-induced refractile morphological changes, detachment of cells from the extracellular matrix, and increased tumor cell motility, invasion, and metastasis. Tumor cells with downregulated FAK activity became less adherent to the extracellular matrix. However, once cells started reattaching, FAK activity was restored by activated integrin signaling. Moreover, this process of readhesion and spreading could not be abrogated by further EGF stimulation. Interruption of transforming growth factor alpha-EGFR autocrine regulation with an EGFR tyrosine kinase inhibitor led to a substantial increase in FAK tyrosine phosphorylation and inhibition of tumor cell invasion in vitro. Consistent with this, FAK tyrosine phosphorylation was reduced in cells from tumors growing in transplanted, athymic, nude mice, which have an intact autocrine regulation of the EGFR. We suggest that the dynamic regulation of FAK activity, initiated by EGF-induced downregulation of FAK leading to cell detachment and increased motility and invasion, followed by integrin-dependent reactivation during readhesion, plays a role in EGF-associated tumor invasion and metastasis.

MeSH Terms
3T3 Cells Alu Elements Animals Base Sequence Cell Adhesion/drug effects,physiology Cell Movement/drug effects,physiology Cytoskeletal Proteins/metabolism DNA Primers/genetics Down-Regulation/drug effects Epidermal Growth Factor/pharmacology ErbB Receptors/physiology Focal Adhesion Kinase 1 Focal Adhesion Protein-Tyrosine Kinases Humans Mice Mice, Nude Neoplasm Invasiveness/physiopathology Neoplasm Metastasis/physiopathology Paxillin Phenotype Phosphoproteins/metabolism Phosphorylation Protein-Tyrosine Kinases/antagonists & inhibitors,chemistry,genetics,metabolism Proteins Retinoblastoma-Like Protein p130 Tumor Cells, Cultured
Chemicals
Cytoskeletal Proteins DNA Primers PXN protein, human Paxillin Phosphoproteins Proteins Pxn protein, mouse Retinoblastoma-Like Protein p130 Epidermal Growth Factor FAK-related nonkinase ErbB Receptors Protein-Tyrosine Kinases Focal Adhesion Kinase 1 Focal Adhesion Protein-Tyrosine Kinases PTK2 protein, human Ptk2 protein, mouse
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Lu Z
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Jiang G
Blume-Jensen P
Hunter T
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.21.12.4016-4031.2001
Published
2001-06-00
Pages
4016-31
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC87064
Subset
IM
Grants
NCI NIH HHS · P30 CA014195 · United States
NCI NIH HHS · CA14195 · United States
NCI NIH HHS · CA82863 · United States
External Links
PubMed source DOI: 10.1128/MCB.21.12.4016-4031.2001 PMC Full Text View journal details
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