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PMID:15899872

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Citation

Wang, SE, Wu, FY, Shin, I, Qu, S and Arteaga, CL (2005) Transforming growth factor {beta} (TGF-{beta})-Smad target gene protein tyrosine phosphatase receptor type kappa is required for TGF-{beta} function. Mol. Cell. Biol. 25:4703-15

Abstract

Transforming growth factor beta (TGF-beta) inhibits proliferation and promotes cell migration. In TGF-beta-treated MCF10A mammary epithelial cells overexpressing HER2 and by chromatin immunoprecipitation, we identified novel Smad targets including protein tyrosine phosphatase receptor type kappa (PTPRK). TGF-beta up-regulated PTPRK mRNA and RPTPkappa (receptor type protein tyrosine phosphatase kappa, the protein product encoded by the PTPRK gene) protein in tumor and nontumor mammary cells; HER2 overexpression down-regulated its expression. RNA interference (RNAi) of PTPRK accelerated cell cycle progression, enhanced response to epidermal growth factor (EGF), and abrogated TGF-beta-mediated antimitogenesis. Endogenous RPTPkappa associated with EGF receptor and HER2, resulting in suppression of basal and ErbB ligand-induced proliferation and receptor phosphorylation. In MCF10A/HER2 cells, TGF-beta enhanced cell motility, FAK phosphorylation, F-actin assembly, and focal adhesion formation and inhibited RhoA activity. These responses were abolished when RPTPkappa was eliminated by RNA interference (RNAi). In cells expressing RPTPkappa RNAi, phosphorylation of Src at Tyr527 was increased and (activating) phosphorylation of Src at Tyr416 was reduced. These data suggest that (i) RPTPkappa positively regulates Src; (ii) HER2 signaling and TGF-beta-induced RPTPkappa converge at Src, providing an adequate input for activation of FAK and increased cell motility and adhesion; and (iii) RPTPkappa is required for both the antiproliferative and the promigratory effects of TGF-beta.

Links

PubMed PMC1140650 Online version:10.1128/MCB.25.11.4703-4715.2005

Keywords

Actins/metabolism; Breast Neoplasms/enzymology; Breast Neoplasms/genetics; Breast Neoplasms/metabolism; Cell Adhesion/genetics; Cell Adhesion/physiology; Cell Movement/genetics; Cell Movement/physiology; Cells, Cultured; DNA-Binding Proteins/metabolism; Epidermal Growth Factor/metabolism; Female; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Humans; Mammary Glands, Human/cytology; Mammary Glands, Human/enzymology; Mammary Glands, Human/metabolism; Phosphorylation; Protein Tyrosine Phosphatases/genetics; Protein Tyrosine Phosphatases/metabolism; Protein Tyrosine Phosphatases/physiology; Protein-Tyrosine Kinases/metabolism; RNA Interference; Receptor, erbB-2/metabolism; Receptor-Like Protein Tyrosine Phosphatases, Class 2; Signal Transduction; Smad Proteins; Trans-Activators/metabolism; Transforming Growth Factor beta/physiology; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism; Tumor Suppressor Proteins/physiology; Up-Regulation; src-Family Kinases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PTPRK

involved_in

GO:0045786: negative regulation of cell cycle

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PTPRK

involved_in

GO:0007179: transforming growth factor beta receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PTPRK

part_of

GO:0031256: leading edge membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PTPRK

involved_in

GO:0008285: negative regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PTPRK

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P04626

F

Seeded From UniProt

complete

HUMAN:PTPRK

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P00533

F

Seeded From UniProt

complete

HUMAN:PTPRK

involved_in

GO:0048041: focal adhesion assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PTPRK

involved_in

GO:0016477: cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PTPRK

involved_in

GO:0007155: cell adhesion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EGFR_original

GO:0019903: protein phosphatase binding

IPI: Inferred from Physical Interaction: UniProtKB:Q15262

F


HUMAN:EGFR

enables

GO:0019903: protein phosphatase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15262

F

Seeded From UniProt

complete

HUMAN:ERBB2

enables

GO:0019903: protein phosphatase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15262

F

Seeded From UniProt

complete


See also

References

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