Regulation of protein tyrosine phosphatase 1B by sumoylation

Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Nature Cell Biology (Impact Factor: 19.68). 02/2007; 9(1):80-5. DOI: 10.1038/ncb1522
Source: PubMed


Protein-tyrosine phosphatase 1B (PTP1B) is an ubiquitously expressed enzyme that negatively regulates growth-factor signalling and cell proliferation by binding to and dephosphorylating key receptor tyrosine kinases, such as the insulin receptor. It is unclear how the activity of PTP1B is regulated. Using a yeast two-hybrid assay, a protein inhibitor of activated STAT1 (PIAS1) was isolated as a PTP1B-interacting protein. Here, we show that PIAS1, which functions as a small ubiquitin-like modifier (SUMO) E3 ligase, associates with PTP1B in mammalian fibroblasts and catalyses sumoylation of PTP1B. Sumoylation of PTP1B reduces its catalytic activity and inhibits the negative effect of PTP1B on insulin receptor signalling and on transformation by the oncogene v-crk. Insulin-stimulated sumoylation of endogenous PTP1B results in a transient downregulation of the enzyme; this event does not occur when the endogenous enzyme is replaced with a sumoylation-resistant mutant of PTP1B. These results suggest that sumoylation, which has been implicated primarily in processes in the nucleus and nuclear pore, also modulates a key enzyme-substrate signalling complex that regulates metabolism and cell proliferation.

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    • "Phosphorylation of STAT3 is mediated by the Janus-activated kinase (JAK) (Zhong and Darnell, 1994); and in a KRAS-induced mouse model of PDAC, a selective JAK2 inhibitor blocked STAT3 phosphorylation and reduced the formation of pancreatic intraepithelial neoplasms and adenocarcinomas (Corcoran et al, 2011). Prior studies have found that the endogenous JAK2 inhibitor protein tyrosine phosphatase 1B (PTP1B) can become sumoylated and inactivated in mammalian fibroblasts (Dadke et al, 2007). The PIAS4 siRNA knockdown cells showed a global decrease in SUMO1 levels. "
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    ABSTRACT: Background: The PIAS4 protein belongs to the family of protein inhibitors of activated STAT, but has since been implicated in various biological activities including the post-translational modification known as sumoylation. In this study, we explored the roles of PIAS4 in pancreatic tumourigenesis. Methods: The expression levels of PIAS4 in pancreatic cancer cells were examined. Cell proliferation and invasion was studied after overexpression and gene silencing of PIAS4. The effect of PIAS4 on hypoxia signalling was investigated. Results: The protein was overexpressed in pancreatic cancer cells compared with the normal pancreas. Gene silencing by PIAS4 small interfering RNA (siRNA) suppressed pancreatic cancer cell growth and overexpression of PIAS4 induced expression of genes related to cell growth. The overexpression of PIAS4 is essential for the regulation of the hypoxia signalling pathway. PIAS4 interacts with the tumour suppressor von Hippel-Lindau (VHL) and leads to VHL sumoylation, oligomerization, and impaired function. Pancreatic cancer cells (Panc0327, MiaPaCa2) treated with PIAS4 siRNA suppressed expression of the hypoxia-inducible factor hypoxia-inducible factor 1 alpha and its target genes JMJD1A, VEGF, and STAT3. Conclusion: Our study elucidates the role of PIAS4 in the regulation of pancreatic cancer cell growth, where the suppression of its activity represents a novel therapeutic target for pancreatic cancers.
    Full-text · Article · Sep 2013 · British Journal of Cancer
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    • "Although most SUMOylation substrates identified so far are nuclear proteins, the enzymes involved in SUMOylation are indeed present in the cytoplasm (Melchior et al., 2003; Johnson, 2004; Geiss-Friedlander and Melchior, 2007). Several pieces of evidence suggested distinct roles for SUMOylation in several cytoplasmic compartments, including mitochondria (Harder et al., 2004; Zunino et al., 2007) and ER (Dadke et al., 2007). SUMOylation is also implicated in regulating intermediate filament (Kaminsky et al., 2009), membrane receptors, and ion channels (Rajan et al., 2005; Benson et al., 2007; Martin et al., 2007). "
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    ABSTRACT: Primary cilia serve as cellular antenna for various sensory signaling pathways. However, how the sensory receptors are properly targeted to the ciliary surface remains poorly understood. Here, we show that UBC-9, the sole E2 small ubiquitin-like modifier (SUMO)-conjugating enzyme, physically interacts with and SUMOylates the C terminus of small GTPase ARL-13, the worm orthologue of ARL13B that mutated in ciliopathy Joubert syndrome. Mutations that totally abolish the SUMOylation of ARL-13 do not affect its established role in ciliogenesis, but fail to regulate the proper ciliary targeting of various sensory receptors and consequently compromise the corresponding sensory functions. Conversely, constitutively SUMOylated ARL-13 fully rescues all ciliary defects of arl-13-null animals. Furthermore, SUMOylation modification of human ARL13B is required for the ciliary entry of polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease. Our data reveal a novel but conserved role for the SUMOylation modification of ciliary small GTPase ARL13B in specifically regulating the proper ciliary targeting of various sensory receptors.
    Preview · Article · Nov 2012 · The Journal of Cell Biology
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    • "PIAS1 has also been shown to associate with protein-tyrosine phosphatase 1B (PTP1B) and to catalyze its sumoylation, which resulted in down-regulation of the phosphatase activity and inhibited dephosphorylation of the insulin receptor. PIAS1-mediated negative regulation of PTP1B was reversed by SENP1, an isopeptidase that was also shown to regulate sumoylation of STAT5 [18,28]. Senp1 knock out mice were found to have severe defects in early T and B cell development. "
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    ABSTRACT: Background STAT1 is an essential transcription factor for interferon-γ-mediated gene responses. A distinct sumoylation consensus site (ψKxE) 702IKTE705 is localized in the C-terminal region of STAT1, where Lys703 is a target for PIAS-induced SUMO modification. Several studies indicate that sumoylation has an inhibitory role on STAT1-mediated gene expression but the molecular mechanisms are not fully understood. Results Here, we have performed a structural and functional analysis of sumoylation in STAT1. We show that deconjugation of SUMO by SENP1 enhances the transcriptional activity of STAT1, confirming a negative regulatory effect of sumoylation on STAT1 activity. Inspection of molecular model indicated that consensus site is well exposed to SUMO-conjugation in STAT1 homodimer and that the conjugated SUMO moiety is directed towards DNA, thus able to form a sterical hindrance affecting promoter binding of dimeric STAT1. In addition, oligoprecipitation experiments indicated that sumoylation deficient STAT1 E705Q mutant has higher DNA-binding activity on STAT1 responsive gene promoters than wild-type STAT1. Furthermore, sumoylation deficient STAT1 E705Q mutant displayed enhanced histone H4 acetylation on interferon-γ-responsive promoter compared to wild-type STAT1. Conclusions Our results suggest that sumoylation participates in regulation of STAT1 responses by modulating DNA-binding properties of STAT1.
    Full-text · Article · Oct 2012 · BMC Biochemistry
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