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SHP-2 can suppress transformation induced by platelet-derived growth factor
A Jazayeri1, J McGee, T Shimamura
1Wayne State University, Detroit, Michigan 48202, USA.
Abstract:
Signaling by either the type alpha or type beta receptors of platelet-derived growth factor occurs by phosphorylation of at least 10 intra-cytoplasmic tyrosine residues and their subsequent association of secondary signaling molecules with Src homology 2 (SH2) domains. Although the role of several of these secondary signaling molecules in mitogenesis has become increasingly clear, their roles in morphological transformation are not as well defined. Here we present evidence that the SHP-2 phosphatase which associates with Tyr 1009 of the type beta receptor and Tyr 720 of the type alpha receptor may suppress transformation induced by the PDGF B chain. Cotransfection of a dominant negative mutant of the SHP-2 gene and the PDGF B chain gene into mouse fibroblasts that only poorly formed foci with the PDGF B chain alone resulted in larger and more prominent foci. Furthermore, introduction of a wild-type copy of the SHP-2 gene into a tumor cell line, U-87MG, which relies on PDGF expression to form foci in vitro, caused a reversion of phenotype.
Insights
SHP-2 phosphatase suppresses platelet-derived growth factor (PDGF)-induced cell transformation. Inhibiting SHP-2 enhances PDGF-driven cell proliferation and focus formation, while its reintroduction reverses these effects.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Platelet-derived growth factor (PDGF) signaling involves receptor phosphorylation and recruitment of SH2 domain-containing molecules.
- The role of these signaling molecules in cell proliferation (mitogenesis) is known, but their role in morphological transformation is less clear.
Purpose of the Study:
- To investigate the role of SHP-2 phosphatase in PDGF-induced cell transformation.
- To determine if SHP-2 suppresses or promotes morphological transformation mediated by PDGF.
Main Methods:
- Cotransfection of dominant-negative SHP-2 and PDGF B chain genes into mouse fibroblasts.
- Introduction of wild-type SHP-2 gene into U-87MG tumor cells.
- Assessment of focus formation and phenotypic changes.
Main Results:
- Cotransfection with dominant-negative SHP-2 enhanced PDGF B chain-induced focus formation in fibroblasts.
- Introduction of wild-type SHP-2 into U-87MG cells reverted their transformed phenotype.
- SHP-2 associates with specific tyrosine residues on PDGF receptors (Tyr 1009 on beta, Tyr 720 on alpha).
Conclusions:
- SHP-2 phosphatase plays a suppressive role in PDGF-induced cell transformation.
- Modulating SHP-2 activity can impact the oncogenic potential of PDGF signaling.