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*

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 AMPKα2 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. 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 AMPKα2 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. The insulin receptor (IR) 1The abbreviations used are:IFinsulin receptorATIC5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolasePTPLAD1protein-tyrosine phosphatase-like A domain-containing protein 1IMPinositol monophosphateAMPadenosine monophosphateAMPKAMP-activated protein kinaseAICAR5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside. 1The abbreviations used are:IFinsulin receptorATIC5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolasePTPLAD1protein-tyrosine phosphatase-like A domain-containing protein 1IMPinositol monophosphateAMPadenosine monophosphateAMPKAMP-activated protein kinaseAICAR5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside. (1Hubbard S.R. Structural biology: insulin meets its receptor.Nature. 2013; 493: 171-172Crossref PubMed Scopus (10) Google Scholar, 2Ward C.W. Menting J.G. Lawrence M.C. The insulin receptor changes conformation in unforeseen ways on ligand binding: sharpening the picture of insulin receptor activation.Bioessays. 2013; 35: 945-954Crossref PubMed Scopus (63) Google Scholar) activates its tyrosine kinase activity through cross-phosphorylation upon insulin binding, which initiates subsequent signaling and metabolic events (3Taniguchi C.M. Emanuelli B. Kahn C.R. Critical nodes in signaling pathways: insights into insulin action.Nat. Rev. Mol. Cell Biol. 2006; 7: 85-96Crossref PubMed Scopus (2081) Google Scholar). The activated complexes are internalized into the endosomal apparatus within seconds following insulin binding (4Posner B.I. Bergeron J.J. Assessment of internalization and endosomal signaling: studies with insulin and EGF.Methods Enzymol. 2014; 535: 293-307Crossref PubMed Scopus (7) Google Scholar). Some factors that govern IR endocytosis have been previously described. For instances topogenic sequences in the juxtamembrane region (GPLY and NPEY) are necessary but not sufficient for rapid endocytosis. The IR tyrosine kinase activity is necessary for the autophosphorylation and exposure of the otherwise buried endocytosis sequences (for a review, see (5McClain D.A. Mechanism and role of insulin receptor endocytosis.Am. J. Med. Sci. 1992; 304: 192-201Crossref PubMed Scopus (21) Google Scholar)). IR autophosphorylation is thought to release a constraint that maintains IR on the microvilli and that allows free, mobile insulin-bound IRs to reach specialized surfaces where endocytosis and signaling are allowed and initiated (6Carpentier J.L. McClain D. Insulin receptor kinase activation releases a constraint maintaining the receptor on microvilli.J. Biol. Chem. 1995; 270: 5001-5006Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 7Vainio S. Heino S. Mansson J.E. Fredman P. Kuismanen E. Vaarala O. Ikonen E. Dynamic association of human insulin receptor with lipid rafts in cells lacking caveolae.EMBO Rep. 2002; 3: 95-100Crossref PubMed Scopus (142) Google Scholar). The interaction with the actin cytoskeleton is an important element as IR compartmentalization at the microvilli on the surface of hepatocytes depends on its coupling with actin (8Lange K. Brandt U. Gartzke J. Bergmann J. Action of insulin on the surface morphology of hepatocytes: role of phosphatidylinositol 3-kinase in insulin-induced shape change of microvilli.Exp. Cell Res. 1998; 239: 139-151Crossref PubMed Scopus (27) Google Scholar, 9Carpentier J.L. Robert Feulgen Prize Lecture 1993. The journey of the insulin receptor into the cell: from cellular biology to pathophysiology.Histochemistry. 1993; 100: 169-184Crossref PubMed Scopus (37) Google Scholar). IR has also been observed in caveolin-enriched hepatic plasma membrane domains that rapidly associate with the actin cytoskeleton in response to insulin (10Balbis A. Baquiran G. Mounier C. Posner B.I. Effect of insulin on caveolin-enriched membrane domains in rat liver.J. Biol. Chem. 2004; 279: 39348-39357Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). By contrast with the EGF receptor (EGFR, a low recycling receptor), the IR is a rapid recycling receptor in liver and this is important both for insulin signaling and clearance (11Bergeron J.J. Di Guglielmo G.M. Baass P.C. Authier F. Posner B.I. Endosomes, receptor tyrosine kinase internalization, and signal transduction.Biosci. Rep. 1995; 15: 411-418Crossref PubMed Scopus (47) Google Scholar, 12Duckworth W.C. Bennett R.G. Hamel F.G. Insulin degradation: progress and potential.Endocr. Rev. 1998; 19: 608-624Crossref PubMed Scopus (684) Google Scholar). The molecular mechanisms underlying IR regulation remain largely unknown. insulin receptor 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase protein-tyrosine phosphatase-like A domain-containing protein 1 inositol monophosphate adenosine monophosphate AMP-activated protein kinase 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside. insulin receptor 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase protein-tyrosine phosphatase-like A domain-containing protein 1 inositol monophosphate adenosine monophosphate AMP-activated protein kinase 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside. Emerging evidence indicates that for coping with cellular and organismal needs the vesicular transport of proteins and lipids to particular regions of the cell, requires plasma membrane and endosome-based signaling devices that would coordinate membrane traffic in response to extracellular signals (13Di Fiore P.P. De Camilli P. Endocytosis and signaling. An inseparable partnership.Cell. 2001; 106: 1-4Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, A. Endocytosis of receptor tyrosine Biol. 2013; PubMed Scopus Google Scholar, a in of signal Cell Biol. 2004; PubMed Scopus Google Scholar, A. The of membrane transport and J. 2006; PubMed Scopus Google Scholar). The of and the molecular of have the we an IR protein interaction network in hepatic We found within the of the internalized IR with the presence of ATIC, a metabolic enzyme of the de novo purine The de novo purine with and with inositol monophosphate are the of and but are also found in and are a of ATP and for metabolic and signaling and Scholar). ATIC, is the enzyme in this and is a enzyme that a which a to the to the and K. J. K. S. B. J. and in human Med. Biol. 1998; PubMed Scopus (27) Google Scholar). is an activator of the AMPK J.G. 5-aminoimidazole-4-carboxamide A for AMP-activated protein kinase in J. 1995; PubMed Scopus Google Scholar) in a that is to as Cell for PubMed Scopus Google Scholar). ATIC is also a rate-limiting enzyme insulin in a in its activity results in a in purine A. S. The phosphatidylinositol purine Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). and have been observed in with of the level of ATIC activity S. B. P. G. a of purine biosynthesis of J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). We show the presence of mechanism an ATIC protein network and the that acts in regulating IR autophosphorylation and endocytosis. insulin was from EGF was from The following and and Cell and and Cell and The 2 which was the that to in the human extracellular and the the and the IR from The actin was from used The signals an was from of and from from from and with and that the was the the The and the fractions as previously (4Posner B.I. Bergeron J.J. Assessment of internalization and endosomal signaling: studies with insulin and EGF.Methods Enzymol. 2014; 535: 293-307Crossref PubMed Scopus (7) Google Scholar, A. of rat plasma of Cell Biol. PubMed Scopus Google Scholar). The protein of was a with as the protein The was also an of the proteins A. M.C. S. E. of signaling complexes in fractions a of receptor Res. PubMed Scopus Google Scholar) and the A of proteins from the that we in A. M.C. S. E. of signaling complexes in fractions a of receptor Res. PubMed Scopus Google Scholar) was used to the network which was from and interaction The the at A. D. S. A. J. P. P. C. interaction with increased and Res. 2013; PubMed Scopus Google Scholar). the for A. S. D. C. A. J. A. A. C. J. C. J. K. The interaction Res. PubMed Scopus Google Scholar). on the K. J. S. A to PubMed Scopus Google Scholar). and the the and of and protein 7: PubMed Scopus Google Scholar). was performed following a the S. K. a to of in PubMed Scopus Google Scholar). We used a to the regions of proteins with with the receptor (IRGEN) to the that was to that of the internalized We used this with the in J. G. a for PubMed Scopus Google Scholar). The fractions and to and an A. E. Bergeron S. A. G. is with and and insulin PubMed Scopus Google Scholar). on an with an and with a The was for the of the with the of the The at the level and the level to the protein used for and from A a of the was with from to and used to the after for IR endosomal autophosphorylation was as previously (4Posner B.I. Bergeron J.J. Assessment of internalization and endosomal signaling: studies with insulin and EGF.Methods Enzymol. 2014; 535: 293-307Crossref PubMed Scopus (7) Google Scholar) with the following at IR of 2 after insulin in the maintaining the of the The IR autophosphorylation was initiated at ATP to a of 1 ATIC of that was from hepatic was for on the the at the IR was and a was performed EGF receptor was where (4Posner B.I. Bergeron J.J. Assessment of internalization and endosomal signaling: studies with insulin and EGF.Methods Enzymol. 2014; 535: 293-307Crossref PubMed Scopus (7) Google Scholar). was following autophosphorylation and to a HEK293 cells IR and of endocytosis A. E. 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Assessment of internalization and endosomal signaling: studies with insulin and EGF.Methods Enzymol. 2014; 535: 293-307Crossref PubMed Scopus (7) Google Scholar). We the following proteins that with internalized IR complexes after insulin ATIC, and and is a IR that to tyrosine phosphorylation in the activation S.R. The insulin both a and receptor tyrosine Biol. 2013; PubMed Scopus Google Scholar) and IR tyrosine kinase activity in A. D. B. J. of insulin receptor activity the molecular Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. D. J. with results in regulation of tyrosine phosphorylation of the insulin Rep. 2006; 7: PubMed Scopus Google Scholar). protein was previously as a common heritable in type 2 J. of J. Full Text Full Text PDF PubMed Scopus Google Scholar). The have not been previously associated with The was to ATIC, which is a protein that has not been previously to with ATIC a with its substrate the of the cyclohydrolase P. 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Assessment of internalization and endosomal signaling: studies with insulin and EGF.Methods Enzymol. 2014; 535: 293-307Crossref PubMed Scopus (7) Google Scholar) and ATIC was in both the and was a rapid to increase in ATIC for the The ATIC increased to to for both and was with the results of the and PTPLAD1 was also in the and with IR was a rapid and increase in PTPLAD1 to to for both A increase in PTPLAD1 was also observed in response to with the insulin which is also with the results AMPK was in both was a rapid and increase in AMPK that at at for the AMPK phosphorylation the insulin was also a rapid and increase in AMPK that at 2 at for both AMPK to level for both AMPK phosphorylation a but at for the and was a rapid and increase in and phosphorylation that at at for both insulin was also a rapid and increase in phosphorylation that at 2 at for both phosphorylation to level for the insulin The presence of ATIC, and AMPK, but not which is also was in the IR following the of the the results the presence of an response for ATIC, PTPLAD1 and AMPK in also association with the We to the of IR autophosphorylation in we used a previously reconstitution system where 2 following the of insulin in the presence of the of IR IR autophosphorylation a at 2 following the of ATP and to of the of the presence of the protein tyrosine IR autophosphorylation was to that of as a of the of the endosomal activity Baquiran G. 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The phosphatidylinositol purine Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). ATIC and PTPLAD1 affect IR tyrosine ATIC also to phosphorylation and to its rapid compartmentalization in IR complexes. ATIC also in the presence of in IR complexes which is with the ATIC and through AMPK, that was the further PTPLAD1 and insulin stimulation in the presence of actin in the IR complexes we the IR endocytosis and ATIC and PTPLAD1 in HEK293 We used an IR in which cells and after endocytosis Kahn C.R. D.A. A. internalization of insulin requires a in the juxtamembrane region of the insulin receptor Biol. Chem. Full Text PDF PubMed Google Scholar). IR after insulin stimulation and decreased at in cells ATIC and PTPLAD1 knockdown increased markedly IR was observed after insulin and the IR to after a we for which is the cells and to the surface in an B. in the regulation of and liver J. 270: PubMed Google Scholar). was used in the as a to the of the surface The results that the was and that this rapidly after insulin stimulation We that ATIC the insulin response of The was observed for PTPLAD1 a signal was also observed that ATIC and PTPLAD1 the insulin response with an from an to the was to affect through phosphorylation at its AMPK J. J. The of and J. Full Text Full Text PDF PubMed Scopus Google Scholar). the ATIC the phosphorylation this the of ATIC on We to IR endocytosis and to the with AMPK a increase in IR internalization was observed after the cells with AICAR, a in IR We this in IR previously observed in cells K. K. J. K. E. AICAR, an activator of AMP-activated protein the insulin receptor in Res. PubMed Scopus Google Scholar). after The AMPKα2 is the to AMPK which is not for the (for a review, see B. Mounier B. E. S. S. J. C. F. from and PubMed Scopus Google Scholar)). we AMPKα2 to AMPKα2 affect IR internalization with The results that AMPKα2 knockdown decreased IR internalization ATIC, and AMPK are of IR internalization in HEK293 A in the of ATIC is to has the to affect the of IR internalization in the for IR in the fractions after the of insulin we found that the of IR endocytosis was with a in IR level observed in the A increase in IR internalization was observed in the with further increase 2 after insulin and with a the with the results in HEK293 cells, rapidly in the after insulin was not in the the as for is in a rapidly that is not in the fraction. the of with IR in the which was AICAR, is with a previously that is associated with IR in hepatic cells A. E. and receptor in J. PubMed Scopus Google Scholar) the results that markedly the IR internalization as as the rapid of at the surface in The results in this the presence of an ATIC network that proteins PTPLAD1 and AMPK and that IR tyrosine phosphorylation and endocytosis The increase in IR internalization that was observed at and later after PTPLAD1 knockdown in HEK293 cells is with IR tyrosine kinase activity (5McClain D.A. Mechanism and role of insulin receptor endocytosis.Am. J. Med. Sci. 1992; 304: 192-201Crossref PubMed Scopus (21) Google Scholar, J.L. P. surface internalization of the insulin receptor and requires its Sci. 1992; PubMed Scopus Google Scholar). to changes in the actin cytoskeleton that IR autophosphorylation S. Heino S. Mansson J.E. Fredman P. Kuismanen E. Vaarala O. Ikonen E. 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