PMID:22045810

Citation	Sangwan, V, Abella, J, Lai, A, Bertos, N, Stuible, M, Tremblay, ML and Park, M (2011) Protein-tyrosine phosphatase 1B modulates early endosome fusion and trafficking of Met and epidermal growth factor receptors. J. Biol. Chem. 286:45000-13
Abstract	The endoplasmic reticulum-localized non-receptor protein-tyrosine phosphatase 1B (PTP1B) is associated with oncogenic, metabolic, and cytokine-related signaling and functionally targets multiple receptor tyrosine kinases (RTKs) for dephosphorylation. Loss of PTP1B activity leads to enhanced ligand-dependent biological activity of the Met RTK among others. Here, we demonstrate that knockdown of PTP1B or expression of a PTP1B trapping aspartic acid-to-alanine substitution (D/A) mutant delayed ligand-induced degradation of the Met and EGF RTKs. Loss of PTP1B function abrogated trafficking of Met and EGF receptor to Rab5- and phosphatidylinositol 3-phosphate (Pl3P)-positive early endosomes and subsequent trafficking through the degradative pathway. Under these conditions, internalization of the Met and EGF receptors was unaltered, suggesting a block at the level of early endosome formation. We show that the N-ethylmaleimide-sensitive factor (NSF), an essential component of the vesicle fusion machinery, was hyperphosphorylated in PTP1B knockdown or PTP1B D/A-expressing cells and was a target for PTP1B. NSF knockdown phenocopied PTP1B knockdown, demonstrating a mechanism through which PTP1B regulates endocytic trafficking. Finally, we show that PTP1B dephosphorylated NSF and that this interaction was required for physiological RTK trafficking and appropriate attenuation of downstream signaling.
Links	PubMed PMC3247994 Online version:10.1074/jbc.M111.270934
Keywords	Amino Acid Substitution; Endocytosis/physiology; Endosomes/enzymology; Endosomes/genetics; Gene Expression Regulation, Enzymologic/physiology; HeLa Cells; Humans; Mutation, Missense; Phosphatidylinositol Phosphates/genetics; Phosphatidylinositol Phosphates/metabolism; Phosphorylation/physiology; Protein Transport/physiology; Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism; Proto-Oncogene Proteins c-met/genetics; Proto-Oncogene Proteins c-met/metabolism; Receptor, Epidermal Growth Factor/genetics; Receptor, Epidermal Growth Factor/metabolism; Signal Transduction/physiology; Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins/genetics; Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:PTN1	involved_in	GO:0006470: protein dephosphorylation	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PTN1	involved_in	GO:0043407: negative regulation of MAP kinase activity	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PTN1		GO:0033157: regulation of intracellular protein transport	ECO:0000315:		P		Figs. 2AB, 3ABC, 4BC, 5B, and 6B	complete CACAO 2696
HUMAN:PTN1		GO:2000646: positive regulation of receptor catabolic process	ECO:0000315:		P		Fig. 1BC, 4A, S4	complete CACAO 2697
HUMAN:PTN1		GO:0006470: protein dephosphorylation	ECO:0000315:		P		Fig. 1A and Fig. 7A	complete CACAO 2698
HUMAN:PTN1		GO:0043407: negative regulation of MAP kinase activity	ECO:0000315:		P		Fig. 1A and Fig. 4D	complete CACAO 2699
HUMAN:PTN1	involved_in	GO:2000646: positive regulation of receptor catabolic process	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PTN1	involved_in	GO:0033157: regulation of intracellular protein transport	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:NSF	involved_in	GO:0045732: positive regulation of protein catabolic process	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:NSF	involved_in	GO:0006886: intracellular protein transport	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:NSF		GO:0006886: intracellular protein transport	ECO:0000315:		P		Fig. 7BC	complete CACAO 2694
HUMAN:NSF		GO:0045732: positive regulation of protein catabolic process	ECO:0000315:		P		Fig. 7	complete CACAO 2695

References

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