Tumor Suppressor PTEN Inhibits Integrin- and Growth Factor-mediated Mitogen-activated Protein (MAP) Kinase Signaling Pathways

doi:10.1083/jcb.143.5.1375

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© The Rockefeller University Press, 0021-9525/1998//1375 $5.00
The Journal of Cell Biology, Volume 143, Number 5, , 1998 1375-1383

Article

Tumor Suppressor PTEN Inhibits Integrin- and Growth Factor–mediated Mitogen-activated Protein (MAP) Kinase Signaling Pathways

Jianguo Gu, Masahito Tamura, and Kenneth M. Yamada

Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-4370

The tumor suppressor PTEN dephosphorylates focal adhesion kinase(FAK) and inhibits integrin-mediated cell spreading and cellmigration. We demonstrate here that expression of PTEN selectivelyinhibits activation of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. PTENexpression in glioblastoma cells lacking the protein resultedin inhibition of integrin-mediated MAP kinase activation. Epidermalgrowth factor (EGF) and platelet-derived growth factor (PDGF)-induced MAPK activation were also blocked. To determine thespecific point of inhibition in the Ras/Raf/ MEK/ERK pathway,we examined these components after stimulation by fibronectinor growth factors. Shc phosphorylation and Ras activity wereinhibited by expression of PTEN, whereas EGF receptor autophosphorylationwas unaffected. The ability of cells to spread at normal rateswas partially rescued by coexpression of constitutively activatedMEK1, a downstream component of the pathway. In addition, focal contact formation was enhanced as indicated by paxillin staining.The phosphatase domain of PTEN was essential for all of thesefunctions, because PTEN with an inactive phosphatase domaindid not suppress MAP kinase or Ras activity. In contrast toits effects on ERK, PTEN expression did not affect c-Jun NH₂-terminalkinase (JNK) or PDGF-stimulated Akt. Our data suggest thata general function of PTEN is to down-regulate FAK and Shcphosphorylation, Ras activity, downstream MAP kinase activation,and associated focal contact formation and cell spreading.

Key Words: PTEN • integrin • growth factor • MAP kinase • cell spreading

Abbreviations used in this paper: ERK, extracellular signal-related kinase; FAK, focal adhesion kinase; FN, fibronectin; GFP, green fluorescent protein; HA, hemagglutinin; JNK/SAPK, c-jun NH₂-terminal kinase/ stress-activated protein kinase; MAP, mitogen-activated protein; MEK, MAP or ERK kinase.

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