SUMO: Wrestling phosphatase activity

signaling update home

updates

news

research library

Exclusive to Signaling Gateway

PIAS1 downregulates the activity of protein-tyrosine phosphatase 1B (PTP1B) by catalyzing its sumoylation.

Protein-tyrosine phosphatase 1B (PTP1B) functions as a negative regulator of insulin and leptin signal transduction. PTP1B is regulated by phosphorylation, oxidation and proteolysis, but now in Nature Cell Biology, Jonathan Chernoff and colleagues report a new mode of regulation. They identify the small ubiquitin-like modifier (SUMO) E3 ligase PIAS (protein inhibitor of activated STAT1) as a PTP1B-interacting protein that reduces its catalytic activity. This study highlights a new role for sumoylation in the regulation of phosphatase activity and insulin signaling.

Using a yeast two-hybrid assay the authors found that PIAS interacts with PTP1B and catalyzes the sumoylation of endogenous PTP1B at multiple sites. PTP1B was not sumoylated in PIAS1-null mouse embryonic fibroblasts indicating that PIAS is responsible for this modification.

Curiously, PTP1B sumoylation is dependent on its cellular localization; endoplasmic reticulum/nuclear envelope-anchored PTP1B mutants are sumoylated to a greater extent than plasma membrane, cytoplasmic or nuclear PTP1B mutants. In agreement with these findings, PTP1B-GFP undergoes Förster resonance energy transfer (FRET) with mRFP-SUMO in the perinuclear region suggesting that the bulk of PTP1B sumoylation takes place at this location.

Double substitution of the lysine residues at positions 335 and 347 with arginine greatly reduced the degree of PTP1B sumoylation, suggesting that these are the main but not the only sites of modification. A sumoylation-resistant form of PTP1B was obtained only when all four consensus sumoylation sites were mutated.

Next, Chernoff and colleagues examined the effect of sumoylation on PTP1B's activity. They found that sumoylation of wild-type PTP1B drastically reduced its activity against p-nitrophenyl phosphate and the autophosphorylated β-subunit of the insulin receptor, whereas the activity of the sumoylation-resistant mutant was unaffected. Crucially, insulin signaling transiently suppressed the ability of PTP1B to downregulate insulin receptor activity by inducing the sumoylation of PTP1B in a PIAS1-dependent manner. These findings highlight the physiological relevance of PIAS1-catalyzed sumoylation of PTP1B and reveal a novel regulatory mechanism for insulin signaling. The precise molecular mechanism responsible for the decrease in SUMO-modified PTP1B activity remains to be determined; as the authors suggest, sumoylation may induce a conformational change that reduces the phosphatase's ability to interact with substrates.

Monica Hoyos Flight
Cell Migration Gateway

References

Shrikrishna Dadke, Sophie Cotteret, Shu-Chin Yip, Zahara M. Jaffer, Fawaz Haj, Alexey Ivanov, Frank Rauscher III, Ke Shuai, Tony Ng, Benjamin G. Neel & Jonathan Chernoff. Regulation of protein tyrosine phosphatase 1B by sumoylation. Nature Cell Biology 9, 80 - 85 (2006) | Article | PubMed |