Compartmentalized CDK2 is connected with SHP-1 and β-catenin and regulates insulin internalization

Fiset, Annie; Xu, Elaine; Bergeron, Sébastien; Marette, André; Pelletier, Georges; Siminovitch, Katherine A.; Olivier, Martin; Beauchemin, Nicole; Faure, Robert

doi:10.1016/j.cellsig.2011.01.019

Cited by 22 publications

(20 citation statements)

References 53 publications

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“…This was confirmed in Ptpn6 H-KO mice by enhanced liver CC1 tyrosine phosphorylation, representing the first direct genetic evidence that hepatocyte Shp1 plays a negative regulatory role in insulin clearance, most likely via CC1 dephosphorylation. More data will be needed to determine whether Shp1 and CC1 regulate hepatic insulin clearance through a Cdk2/β-catenin pathway as we recently reported in human embryonic kidney 293 cells (38). …”

Section: Discussionmentioning

confidence: 98%

Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance

Charbonneau

Rolland

et al. 2012

Diabetes

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The protein-tyrosine phosphatase Shp1 negatively regulates insulin action on glucose homeostasis in liver and muscle, but its potential role in obesity-linked insulin resistance has not been examined. To investigate the role of Shp1 in hepatic insulin resistance, we generated hepatocyte-specific Shp1 knockout mice ( Ptpn6 H-KO ), which were subjected to extensive metabolic monitoring throughout an 8-week standard chow diet (SD) or high-fat diet (HFD) feeding. We report for the first time that Shp1 expression is upregulated in metabolic tissues of HFD-fed obese mice. When compared with their Shp1-expressing Ptpn6 f/f littermates, Ptpn6 H-KO mice exhibited significantly lowered fasting glycemia and heightened hepatic insulin sensitivity. After HFD feeding, Ptpn6 H-KO mice developed comparable levels of obesity as Ptpn6 f/f mice, but they were remarkably protected from liver insulin resistance, as revealed by euglycemic clamps and hepatic insulin signaling determinations. Although Ptpn6 H-KO mice still acquired diet-induced peripheral insulin resistance, they were less hyperinsulinemic during a glucose tolerance test because of reduced insulin secretion. Ptpn6 H-KO mice also exhibited increased insulin clearance in line with enhanced CC1 tyrosine phosphorylation in liver. These results show that hepatocyte Shp1 plays a critical role in the development of hepatic insulin resistance and represents a novel therapeutic target for obesity-linked diabetes.

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Section: Discussionmentioning

confidence: 98%

Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance

Charbonneau

Rolland

et al. 2012

Diabetes

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“…siRNA Knockdown in HEK293 Cells-HEK293 cells express IR and allow measurements of insulin-mediated endocytosis (31). We used the following predesigned human sequences to deplete ATIC, PTP-LAD1, and AMPK␣2 in HEK293 cells:…”

Section: Methodsmentioning

confidence: 99%

“…Identification of Internalized IR Partners-The G/E fractions were solubilized and subjected to immunoprecipitation and in-gel analysis procedures using an anti-IR antibody (31).…”

Section: Methodsmentioning

confidence: 99%

The Last Enzyme of the De Novo Purine Synthesis Pathway 5-aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase (ATIC) Plays a Central Role in Insulin Signaling and the Golgi/Endosomes Protein Network*

Boutchueng-Djidjou¹,

Collard-Simard²,

Fortier³

et al. 2015

Molecular & Cellular Proteomics

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Insulin is internalized with its cognate receptor into the endosomal apparatus rapidly after binding to hepatocytes. We performed a bioinformatic screen of Golgi/endosome hepatic protein fractions and found that ATIC, which is a rate-limiting enzyme in the de novo purine biosynthesis pathway, and PTPLAD1 are associated with insulin receptor (IR) internalization. The IR interactome (IRGEN) connects ATIC to AMPK within the Golgi/endosome protein network (GEN). Forty-five percent of the IR Golgi/endosome protein network have common heritable variants associated with type 2 diabetes, including ATIC and AMPK. We show that PTPLAD1 and AMPK are rapidly compartmentalized within the plasma membrane (PM) and Golgi/endosome fractions after insulin stimulation and that ATIC later accumulates in the Golgi/endosome fraction. Using an in vitro reconstitution system and siRNA-mediated partial knockdown of ATIC and PTPLAD1 in HEK293 cells, we show that both ATIC and PTPLAD1 affect IR tyrosine phosphorylation and endocytosis. We further show that insulin stimulation and ATIC knockdown readily increase the level of AMPK-Thr172 phosphorylation in IR complexes. We observed that IR internalization was markedly decreased after AMPK␣2 knockdown, and treatment with the ATIC substrate AICAR, which is an allosteric activator of AMPK, increased IR endocytosis in cultured cells and in the liver. These results suggest the presence of a signaling mechanism that senses adenylate synthesis, ATP levels, and IR activation states and that acts in regulating IR autophosphorylation and endocytosis. Molecular & Cellular

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“…Fractions were prepared at the 2-minute time peak of IR accumulation and the 15-minute 50% decline time [15, 18] to collect a larger proteome. Freshly prepared fractions were then incubated with anti-IR (β-subunit)-coated magnetic beads, and endosomes were collected with a magnet [19, 20]. We identified a total of 620 proteins with high confidence (named IREP: IR Endosome Proteome, Fig 1A and S1Table).…”

Section: Resultsmentioning

confidence: 99%

A type 2 diabetes disease module with a high collective influence for Cdk2 and PTPLAD1 is localized in endosomes

Boutchueng-Djidjou

Belleau

Bilodeau

et al. 2018

Preprint

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1Despite the identification of many susceptibility genes our knowledge of the underlying mechanisms 2 responsible for complex disease remains limited. Here, we identified a type 2 diabetes disease 3 module in endosomes, and validate it for functional relevance on selected nodes. Using hepatic 4Golgi/endosomes fractions, we established a proteome of insulin receptor-containing endosomes 5 that allowed the study of physical protein interaction networks on a type 2 diabetes background. 6The resulting collated network is formed by 313 nodes and 1147 edges with a topology organized 7 around a few major hubs with Cdk2 displaying the highest collective influence. Overall, 88% of the 8 nodes are associated with the type 2 diabetes genetic risk, including 101 new candidates. The Type 9 2 diabetes module is enriched with cytoskeleton and luminal acidification -dependent processes that 10 are shared with secretion-related mechanisms. We identified new signaling pathways driven by 11Cdk2 and PTPLAD1 whose expression regulate the association of the insulin receptor with TUBA, 12 TUBB, the actin component ACTB and the endosomal sorting markers Rab5c and Rab11a. 13

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Compartmentalized CDK2 is connected with SHP-1 and β-catenin and regulates insulin internalization

Cited by 22 publications

References 53 publications

Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance

Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance

The Last Enzyme of the De Novo Purine Synthesis Pathway 5-aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase (ATIC) Plays a Central Role in Insulin Signaling and the Golgi/Endosomes Protein Network*

A type 2 diabetes disease module with a high collective influence for Cdk2 and PTPLAD1 is localized in endosomes

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