Artículo

Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

Abstract:

Insulin signaling comprises a complex cascade of events, playing a key role in the regulation of glucose metabolism and cellular growth. Impaired response to insulin is the hallmark of diabetes, whereas upregulated insulin activity occurs in many cancers. Two splice variants of the insulin receptor (IR) exist in mammals: IR-A, lacking exon 11, and full-length IR-B. Although considerable biochemical data exist on insulin binding and downstream signaling, little is known about the dynamics of the IR itself. We created functional IR transgenes fused with visible fluorescent proteins for use in combination with biotinamido-caproyl insulin and streptavidin quantum dots. Using confocal and structured illumination microscopy, we visualized the endocytosis of both isoforms in living and fixed cells and demonstrated a higher rate of endocytosis of IR-A than IR-B. These differences correlated with higher and sustained activation of IR-A in response to insulin and with distinctive ERK1/2 activation profiles and gene transcription regulation. In addition, cells expressing IR-B showed higher AKT phosphorylation after insulin stimulation than cells expressing IR-A. Taken together, these results suggest that IR signaling is dependent on localization; internalized IRs regulate mitogenic activity, whereas metabolic balance signaling occurs at the cell membrane.

Registro:

Documento: Artículo
Título:Differential endocytosis and signaling dynamics of insulin receptor variants IR-A and IR-B
Autor:Giudice, J.; Leskow, F.C.; Arndt-Jovin, D.J.; Jovin, T.M.; Jares-Erijman, E.A.
Filiación:Departamento de Química Orgánica, Universidad de Buenos Aires (UBA), Ciudad Universitaria, Intendente Güiraldes 2160, C1428EGA, Buenos Aires, Argentina
Laboratory of Cellular Dynamics, Max-Planck Institute for Biophysical Chemistry (MPIbpc), D-37077 Göttingen, Germany
Laboratorio de Dinámica Celular, Universidad de Buenos Aires (UBA), Ciudad Universitaria, Intendente Güiraldes 2160, C1428EGA, Buenos Aires, Argentina
Palabras clave:Insulin; Insulin receptor isoforms; Programmable array microscope; Quantum dots; insulin; insulin receptor; insulin receptor ir a; insulin receptor ir b; mitogen activated protein kinase 1; mitogen activated protein kinase 3; protein kinase B; unclassified drug; article; endocytosis; enzyme activation; enzyme phosphorylation; mitogenesis; priority journal; protein localization; receptor upregulation; signal transduction; transcription regulation; Alternative Splicing; Cell Membrane; Endocytosis; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Hela Cells; Humans; Insulin; Protein Isoforms; Proto-Oncogene Proteins c-akt; Pseudopodia; Quantum Dots; Receptor, Insulin; Recombinant Fusion Proteins; Signal Transduction; Transcription Factor AP-1; Transgenes; Mammalia
Año:2011
Volumen:124
Número:5
Página de inicio:801
Página de fin:811
DOI: http://dx.doi.org/10.1242/jcs.076869
Título revista:Journal of Cell Science
Título revista abreviado:J. Cell Sci.
ISSN:00219533
CODEN:JNCSA
CAS:insulin, 9004-10-8; mitogen activated protein kinase 1, 137632-08-7; mitogen activated protein kinase 3, 137632-07-6; protein kinase B, 148640-14-6; Extracellular Signal-Regulated MAP Kinases, 2.7.11.24; Insulin, 11061-68-0; Protein Isoforms; Proto-Oncogene Proteins c-akt, 2.7.11.1; Receptor, Insulin, 2.7.10.1; Recombinant Fusion Proteins; Transcription Factor AP-1
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219533_v124_n5_p801_Giudice

Referencias:

  • Andrews, N.L., Pfeiffer, J.R., Martinez, A.M., Haaland, D.M., Davis, R.W., Kawakami, T., Oliver, J.M., Lidke, D.S., Small, mobile Fc epsilon RI receptor aggregates are signaling competent (2009) Immunity, 31, pp. 469-479
  • Backer, J.M., Kahn, C.R., Cahill, D.A., Ullrich, A., White, M.F., Receptor-mediated internalization of insulin requires a 12-amino acid sequence in the juxtamembrane region of the insulin receptor β-subunit (1990) J. Biol. Chem., 265, pp. 16450-16454
  • Bailyes, E.M., Nave, B.T., Soos, M.A., Orr, S.R., Hayward, A.C., Siddle, K., Insulin receptor/IGF-I receptor hybrids are widely distributed in mammalian tissues: Quantification of individual receptor species by selective immunoprecipitation and immunoblotting (1997) Biochemical Journal, 327 (1), pp. 209-215
  • Benyoucef, S., Surinya, K.H., Hadaschik, D., Siddle, K., Characterization of insulin/IGF hybrid receptors: Contributions of the insulin receptor L2 and Fn1 domains and the alternatively spliced exon 11 sequence to ligand binding and receptor activation (2007) Biochemical Journal, 403 (3), pp. 603-613. , DOI 10.1042/BJ20061709
  • Bergeron, J.J.M., Di, G.G.M., Baass, P.C., Authier, F., Posner, B.I., Endosomes, receptor tyrosine kinase internalization and signal transduction (1995) Bioscience Reports, 15 (6), pp. 411-418. , DOI 10.1007/BF01204345
  • Biener, Y., Feinstein, R., Mayak, M., Kaburagi, Y., Kadowaki, T., Zick, Y., Annexin II is a novel player in insulin signal transduction: Possible association between annexin II phosphorylation and insulin receptor internalization (1996) Journal of Biological Chemistry, 271 (46), pp. 29489-29496. , DOI 10.1074/jbc.271.46.29489
  • Blanquart, C., Achi, J., Issad, T., Characterization of IRA/IRB hybrid insulin receptors using bioluminscence resonance energy transfer (2008) Biochem. Pharmacol., 76, pp. 873-883
  • Borisov, N., Aksamitiene, E., Kiyatkin, A., Legewie, S., Berkhout, J., Maiwald, T., Kaimachnikov, N.P., Kholodenko, B.N., Systems-level interactions between insulin-EGF networks amplify mitogenic signaling (2009) Mol. Syst. Biol., 5, p. 256
  • Cambi, A., Lidke, D.S., Arndt-Jovin, D.J., Figdor, C.G., Jovin, T.M., Ligand-conjugated quantum dots monitor antigen uptake and processing by dendritic cells (2007) Nano Lett., 7, pp. 970-977
  • Ceresa, B.P., Kao, A.W., Santeler, S.R., Pessin, J.E., Inhibition of clathrin mediated endocytosis selectively attenuates specific insulin receptor signal transduction pathways (1998) Mol. Cell. Biol., 18, pp. 3862-3870
  • Denley, A., Bonython, E.R., Booker, G.W., Cosgrove, L.J., Forbes, B.E., Ward, C.W., Wallace, J.C., Structural determinants for high-affinity binding of insulin-like growth factor II to insulin receptor (IR)-A, the exon 11 minus isoform of the IR (2004) Mol. Endocrinol., 18, pp. 2502-2512
  • Di, G.G.M., Baass, P.C., Ou, W.-J., Posner, B.I., Bergeron, J.J.M., Compartmentalization of SHC, GRB2 and mSOS, and hyperphosphorylation of Raf-1 by EGF but not insulin in liver parenchyma (1994) EMBO Journal, 13 (18), pp. 4269-4277
  • Ebina, Y., Ellis, L., Jarnagin, K., The human insulin receptor cDNA: The structural basis for hormone-activated transmembrane signalling (1985) Cell, 40 (4), pp. 747-758
  • Echarte, M.M., Bruno, L., Arndt-Jovin, D.J., Jovin, T.M., Pietrasanta, L.I., Quantitative single particle tracking of NGF-receptor complexes: Transport is bidirectional but biased by longer retrograde run lengths (2007) FEBS Letters, 581 (16), pp. 2905-2913. , DOI 10.1016/j.febslet.2007.05.041, PII S0014579307005698
  • Frasca, F., Pandini, G., Scalia, P., Sciacca, L., Mineo, R., Costantino, A., Goldfine, I.D., Vigneri, R., Insulin receptor isoform A, a newly recognized, high-affinity insulin- Like growth factor II receptor in fetal and cancer cells (1999) Molecular and Cellular Biology, 19 (5), pp. 3278-3288
  • Goldstein, B.J., Dudley, A.L., The rat insulin receptor: Primary structure and conservation of tissue-specific alternative messenger RNA splicing (1990) Mol. Endocrinol., 4, pp. 235-244
  • Grimes, M.L., Zhou, J., Beattie, E.C., Yuen, E.C., Hall, D.E., Valletta, J.S., Topp, K.S., Mobley, W.C., Endocytosis of activated TrkA: Evidence that nerve growth factor induces formation of signaling endosomes (1996) J. Neurosci., 16, pp. 7950-7964
  • Haft, C.R., De La, L.S.M., Hamer, I., Carpentier, J.-L., Taylor, S.I., Analysis of the juxtamembrane dileucine motif in the insulin receptor (1998) Endocrinology, 139 (4), pp. 1618-1629
  • Hagen, G.M., Caarls, W., Thomas, M., Hill, A., Lidke, K., Rieger, B., Fritsch, C., Arndt-Jovin, D.J., Biological applications of an LCoS-based Programmable Array Microscope (PAM) (2007) Proc. SPIE, 6441, pp. 64410S1-6440S12
  • Hagen, G.M., Caarls, W., Lidke, K., De Vries, A.H.B., Fritsch, C., Barisas, B.G., Arndt-Jovin, D.J., Jovin, T.M., Photoconversion and FRAP measurements in arbitrary regions of interest using a Programmable Array Microscope (2009) Microsc. Res. Tech., 72, pp. 431-440
  • Hamer, I., Foti, M., Emkey, R., Cordier-Bussat, M., Philippe, J., De Meyts, P., Maeder, C., Carpentier, J.L., An arginine to cysteine (252) mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalization but preserves signalling events (2002) Diabetologia, 45, pp. 657-667
  • Hari, J., Roth, R.A., Defective internalization of insulin and its receptor in cells expressing mutated insulin receptors lacking kinase activity (1987) J. Biol. Chem., 262, pp. 15341-15344
  • Heintzmann, R., Hanley, Q.S., Arndt-Jovin, D.J., Jovin, T.M., A dual path programmable array microscope (PAM): Simultaneous acquisition of conjugate and non-conjugate images (2001) J. Microsc., 204, pp. 119-135
  • Jensen, M., De Meyts, P., Molecular mechanisms of differential intracellular signaling from the insulin receptor (2009) Vitam. Horm., 80, pp. 51-75
  • Kellerer, M.G., Sesti, G., Seffer, E., Obermaier-Kusser, B., Pongratz, D.E., Mosthaf, L., Häring, H.U., Altered pattern of insulin receptor isotypes in skeletal muscle membranes of type 2 (non-insulin-dependent) diabetic subjects (1993) Diabetologia, 36, pp. 628-632
  • Kremers, G.-J., Goedhart, J., Van Munster, E.B., Gadella Jr., T.W.J., Cyan and yellow super fluorescent proteins with improved brightness, protein folding, and FRET förster radius (2006) Biochemistry, 45 (21), pp. 6570-6580. , DOI 10.1021/bi0516273
  • Lidke, D.S., Nagy, P., Heintzmann, R., Arndt-Jovin, D.J., Post, J., Grecco, H., Jares-Erijman, E.A., Jovin, T.M., Quantum dot ligands reveal EGFR dynamics in living cells (2004) Nat. Biotechnol., 22, pp. 198-203
  • Lidke, D.S., Lidke, K.A., Rieger, B., Jovin, T.M., Arndt-Jovin, D.J., Reaching out for signals: Filopodia sense EGF and respond by directed retrograde transport of activated receptors (2005) Journal of Cell Biology, 170 (4), pp. 619-626. , http://www.jcb.org/cgi/reprint/170/4/619, DOI 10.1083/jcb.200503140
  • Lidke, D.S., Nagy, P., Heintzmann, R., Jovin, T.M., Arndt-Jovin, D.J., Biotin-ligand complexes with streptavidin quantum dots for in vivo cell labeling of membrane receptors (2007) Methods Mol. Biol., 374, pp. 69-80
  • McClain, D.A., Maegawa, H., Lee, J., Dull, T.J., Ullrich, A., Olefsky, J.M., A mutant insulin receptor with defective tyrosine kinase displays no biologic activity and does not undergo endocytosis (1987) J. Biol. Chem., 262, pp. 14663-14671
  • McKeon, C., Moncada, V., Pham, T., Salvatore, P., Kadowaki, T., Accili, D., Taylor, S.I., Structural and functional analysis of the insulin receptor promoter (1990) Mol. Endocrinol., 4, pp. 647-656
  • Mosthaf, L., Grako, K., Dull, T.J., Coussens, L., Ullrich, A., McClain, D.A., Functionally distinct insulin receptors generated by tissue-specific alternative splicing (1990) EMBO J., 9, pp. 2409-2413
  • Mosthaf, L., Vogt, B., Haring, H.U., Ullrich, A., Altered expression of insulin receptor types A and B in the skeletal muscle of non-insulin-dependent diabetes mellitus patients (1991) Proceedings of the National Academy of Sciences of the United States of America, 88 (11), pp. 4728-4730
  • Pandini, G., Vigneri, R., Costantino, A., Frasca, F., Ippolito, A., Fujita-Yamaguchi, Y., Siddle, K., Belfiore, A., Insulin and insulin-like growth factor-I (IGF-I) receptor overexpression in breast cancers leads to insulin/IGF-I hybrid receptor overexpression: Evidence for a second mechanism of IGF-I signaling (1999) Clinical Cancer Research, 5 (7), pp. 1935-1944
  • Pandini, G., Frasca, F., Mineo, R., Sciacca, L., Vigneri, R., Belfiore, A., Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved (2002) Journal of Biological Chemistry, 277 (42), pp. 39684-39695. , DOI 10.1074/jbc.M202766200
  • Papa, V., Gliozzo, B., Clark, G.M., McGuire, W.L., Moore, D., Fujita-Yamaguchi, Y., Vigneri, R., Pezzino, V., Insulin-like growth factor-I receptors are overexpressed and predict a low risk in human breast cancer (1993) Cancer Research, 53 (16), pp. 3736-3740
  • Pastore, S., Mascia, F., Mariotti, F., Dattilo, C., Mariani, V., Girolomoni, G., ERK1/2 regulates epidermal chemokine expression and skin inflammation (2005) J. Immunol., 174, pp. 5047-5056
  • Patti, M.E., Kahn, C.R., The insulin receptor, a critical link in glucose homeostasis and insulin action (1998) J. Basic Clin. Physiol. Pharmacol., 9, pp. 89-109
  • Pol, A., Calvo, M., Enrich, C., Isolated endosomes from quiescent rat liver contain the signal transduction machinery: Differential distribution of activated Raf-1 and Mek in the endocytic compartment (1998) FEBS Letters, 441 (1), pp. 34-38. , DOI 10.1016/S0014-5793(98)01517-8, PII S0014579398015178
  • Reynet, C., Caron, M., Magre, J., Cherqui, G., Clauser, E., Picard, J., Capeau, J., Mutation of tyrosine residues 1162 and 1163 of the insulin receptor affects hormone and receptor internalization (1990) Mol. Endocrinol., 4, pp. 304-311
  • Rizzo, M.A., Shome, K., Watkins, S.C., Romero, G., The recruitment of Raf-1 to membranes is mediated by direct interaction with phosphatidic acid and is independent of association with Ras (2000) Journal of Biological Chemistry, 275 (31), pp. 23911-23918. , DOI 10.1074/jbc.M001553200
  • Russell, D.S., Gherzi, R., Johnson, E.L., Chou, C.K., Rosen, O.M., The protein-tyrosine kinase activity of the insulin receptor is necessary for insulin-mediated receptor down-regulation (1987) J. Biol. Chem., 262, pp. 11833-11840
  • Saltiel, A.R., Kahn, C.R., Insulin signalling and the regulation of glucose and lipid metabolism (2001) Nature, 414 (6865), pp. 799-806. , DOI 10.1038/414799a
  • Savkur, R.S., Philips, A.V., Cooper, T.A., Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy (2001) Nat. Genet., 29, pp. 40-47
  • Sebastian, S., Settleman, J., Reshkin, S.J., Azzariti, A., Bellizzi, A., Paradiso, A., The complexity of targeting EGFR signalling in cancer: From expression to turnover (2006) Biochimica et Biophysica Acta - Reviews on Cancer, 1766 (1), pp. 120-139. , DOI 10.1016/j.bbcan.2006.06.001, PII S0304419X06000321
  • Seino, S., Bell, G.I., Alternative splicing of human insulin receptor messenger RNA (1989) Biochemical and Biophysical Research Communications, 159 (1), pp. 312-316. , DOI 10.1016/0006-291X(89)92439-X
  • Sen, S., Talukdar, I., Webster, N.J.G., SRp20 and CUG-BP1 modulate insulin receptor exon 11 alternative splicing (2009) Mol. Cell. Biol., 29, pp. 871-880
  • Sorkin, A., Eriksson, A., Heldin, C.-H., Westermark, B., Claesson-Welsh, L., Pool of ligand-bound platelet-derived growth factor beta-receptors remain activated and tyrosine phosphorylated after internalization (1993) Journal of Cellular Physiology, 156 (2), pp. 373-382
  • Sorkin, A., McClure, M., Huang, F., Carter, R., Interaction of EGF receptor and grb2 in living cells visualized by fluorescence resonance energy transfer (FRET) microscopy (2000) Curr. Biol., 10, pp. 1395-1398
  • Thies, R.S., Webster, N.J., McClain, D.A., A domain of the insulin receptor required for endocytosis in rat fibroblasts (1990) J. Biol. Chem., 265, pp. 10132-10137
  • Uhles, S., Moede, T., Leibiger, B., Berggren, P.O., Leibiger, I.B., Isoform-specific insulin receptor signaling involves different plasma membrane domains (2003) J. Cell Biol., 163, pp. 1327-1337
  • Ullrich, A., Bell, J.R., Chen, E.Y., Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes (1985) Nature, 313 (6005), pp. 756-761. , DOI 10.1038/313756a0
  • Vogt, B., Carrascosa, J.M., Ermel, B., Ullrich, A., Haring, H.U., The two isotypes of the human insulin receptor (HIR-A and HIR-B) follow different internalization kinetics (1991) Biochem. Biophys. Res. Commun., 177, pp. 1013-1018
  • Ward, C.W., Lawrencea, M.C., Streltsova, V.A., Adams, T.E., McKern, N.M., The insulin and EGF receptor structures: New insights into ligand-induced receptor activation (2007) Trends Biochem. Sci., 32, pp. 129-137
  • White, M.F., The IRS-signalling system: A network of docking proteins that mediate insulin action (1998) Mol. Cell. Biochem., 182, pp. 3-11
  • Wilden, P.A., Backer, J.M., Kahn, C.R., Cahill, D.A., Schroeder, G.J., White, M.F., The insulin receptor with phenylalanine replacing tyrosine-1146 provides evidence for separate signals regulating cellular metabolism and growth (1990) Proc. Natl. Acad. Sci. USA, 87, pp. 3358-3362
  • Yamaguchi, Y., Flier, J.S., Yokota, A., Benecke, H., Backer, J.M., Moller, D.E., Functional properties of two naturally occurring isoforms of the human insulin receptor in Chinese hamster ovary cells (1991) . Endocrinology, 129, pp. 2058-2066
  • Yamaguchi, Y., Flier, J.S., Benecke, H., Ransil, B.J., Moller, D.E., Ligand-binding properties of the two isoforms of the human insulin receptor (1993) Endocrinology, 132, pp. 1132-1138
  • Yamamoto-Honda, R., Koshio, O., Tobe, K., Shibasaki, Y., Momomura, K., Odawara, M., Kadowaki, T., Kasuga, M., Phosphorylation state and biological function of a mutant human insulin receptor val996 (1990) J. Biol. Chem., 265, pp. 14777-14783

Citas:

---------- APA ----------
Giudice, J., Leskow, F.C., Arndt-Jovin, D.J., Jovin, T.M. & Jares-Erijman, E.A. (2011) . Differential endocytosis and signaling dynamics of insulin receptor variants IR-A and IR-B. Journal of Cell Science, 124(5), 801-811.
http://dx.doi.org/10.1242/jcs.076869
---------- CHICAGO ----------
Giudice, J., Leskow, F.C., Arndt-Jovin, D.J., Jovin, T.M., Jares-Erijman, E.A. "Differential endocytosis and signaling dynamics of insulin receptor variants IR-A and IR-B" . Journal of Cell Science 124, no. 5 (2011) : 801-811.
http://dx.doi.org/10.1242/jcs.076869
---------- MLA ----------
Giudice, J., Leskow, F.C., Arndt-Jovin, D.J., Jovin, T.M., Jares-Erijman, E.A. "Differential endocytosis and signaling dynamics of insulin receptor variants IR-A and IR-B" . Journal of Cell Science, vol. 124, no. 5, 2011, pp. 801-811.
http://dx.doi.org/10.1242/jcs.076869
---------- VANCOUVER ----------
Giudice, J., Leskow, F.C., Arndt-Jovin, D.J., Jovin, T.M., Jares-Erijman, E.A. Differential endocytosis and signaling dynamics of insulin receptor variants IR-A and IR-B. J. Cell Sci. 2011;124(5):801-811.
http://dx.doi.org/10.1242/jcs.076869