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Shc and FAK differentially regulate cell motility and directionality modulated by PTEN
1Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-4370, USA.
The Journal of Cell Biology
|July 31, 1999
Summary
Tumor suppressor PTEN regulates cell migration by downmodulating two pathways: one involving Shc and MAP kinase for random motility, and another with FAK and p130(Cas) for directional movement.
Area of Science:
- Cell Biology
- Molecular Oncology
Background:
- Cell migration is crucial for development and disease, influenced by molecules like PTEN.
- PTEN normally inhibits cell migration; FAK and p130(Cas) restore motility.
- Previous work identified FAK and p130(Cas) in directional cell migration.
Purpose of the Study:
- To identify novel pathways regulating random cell motility.
- To elucidate the role of Shc and MAP kinase in PTEN-modulated cell migration.
- To understand how PTEN integrates pathways controlling cell speed and directionality.
Main Methods:
- Utilized PTEN-reconstituted U87-MG cells.
- Overexpressed Shc, MEK1, dominant-negative Shc, and examined Akt.
- Investigated integrin-mediated signaling and cell migration.
- Assessed actin microfilament and focal adhesion organization.
Main Results:
- A novel pathway involving Shc and MAP kinase regulates random cell motility, downregulated by PTEN.
- This Shc/MAPK pathway is additive to the FAK/p130(Cas) pathway controlling directional migration.
- PTEN directly dephosphorylates Shc, inhibiting random migration.
- FAK/p130(Cas) pathway drives persistent, directional migration with extensive cytoskeletal organization.
- Shc/MEK1 pathway drives random migration with less cytoskeletal organization.
Conclusions:
- Identified two distinct, additive PTEN-regulated pathways controlling cell migration: Shc/MAPK for random motility and FAK/p130(Cas) for directional motility.
- PTEN's regulation of these pathways provides an intracellular mechanism for controlling cell migration speed and directionality.
- These findings offer insights into cancer cell motility and potential therapeutic targets.
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