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Novel roles for insulin receptor (IR) in adipocytes and skeletal muscle cells via new and unexpected substrates

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Abstract

The insulin signaling pathway regulates whole-body glucose homeostasis by transducing extracellular signals from the insulin receptor (IR) to downstream intracellular targets, thus coordinating a multitude of biological functions. Dysregulation of IR or its signal transduction is associated with insulin resistance, which may culminate in type 2 diabetes. Following initial stimulation of IR, insulin signaling diverges into different pathways, activating multiple substrates that have roles in various metabolic and cellular processes. The integration of multiple pathways arising from IR activation continues to expand as new IR substrates are identified and characterized. Accordingly, our review will focus on roles for IR substrates as they pertain to three primary areas: metabolism/glucose uptake, mitogenesis/growth, and aging/longevity. While IR functions in a seemingly pleiotropic manner in many cell types, through these three main roles in fat and skeletal muscle cells, IR multi-tasks to regulate whole-body glucose homeostasis to impact healthspan and lifespan.

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Abbreviations

Akt:

Protein kinase B

aP2:

Adipocyte protein 2

APS:

Adapter protein with pleckstrin homology and Src homology domain

Arp2/3:

Actin-related protein 2/3

AS160:

Akt substrate of 160 kDa

BAIRKO:

Brown adipocyte-specific insulin receptor knockout

CAP:

c-Cbl-associated protein

Cav-1:

Caveolin-1

Cav-3:

Caveolin-3

CHO:

Chinese hamster ovary cells

CIP4:

Cdc42-interacting protein

CrkII:

CT10-related kinase

Erk1/2:

Extracellular signal regulated kinases 1 or 2

FIRKO:

Fat-specific muscle insulin receptor knockout

FOXO:

Forkhead box protein O-1

Gab-1:

Grb2-associated binding protein

GIRKI:

GLUT4-expressing tissues insulin receptor knock-in mouse

GIRKO:

GLUT4-expressing tissues insulin receptor knockout

GLUT4:

Glucose transporter 4

Grb2:

Growth factor receptor bound 2

Grb10:

Growth factor receptor bound 10

HR:

Hybrid receptor

IGF:

Insulin-like growth factor

IGFR:

Insulin-like growth factor receptor

IR:

Insulin receptor

IRS-1/2:

Insulin receptor substrate-1 or 2

Jak-1:

Janus kinase-1

L1:

Ligand binding domain 1

L2:

Ligand binding domain 2

LAR:

Leukocyte antigen related

LRP:

Lipoprotein receptor-related protein

MAPK:

Mitogen-activated protein kinase

MIRKO:

Muscle-specific muscle insulin receptor knockout

MD1/2:

Mytonic dystrophy

mTOR:

Mammalian target of rapamycin

N-Wasp:

Neuronal Wiskott–Aldrich syndrome protein

PC-1:

Plasma cell membrane glycoprotein-1

PDK-1:

Phosphoinsitide-dependent protein kinase 1

PH:

Pleckstrin homology

PI3-K:

Phosphoinositide 3-kinase

PIP3:

Phosphatidylinositol (3, 4, 5)-triphosphate

PKC:

Protein kinase C

PM:

Plasma membrane

PP63:

Phosphoprotein of 63 kDa

PTB:

Phosphotyrosine binding domain

PTP1B:

Protein tyrosine phosphatase 1B

p21Ras :

Rat sarcoma protein (Ras)

SAIN:

Shc and IRS NPXY binding domain

SERCA:

Sarcoplasmic/endoplasmic reticulum calcium ATPase

SH2:

Src homology 2

Shc:

Src homology-containing protein

SHP:

SH2-containing tyrosine phosphatase

SirT:

Sirtuins

SNARE:

Soluble N-ethylmaleimide-sensitive factor attachment receptor

SOCS-3:

Suppressor of cytokine signaling 3

SOS:

Son of Sevenless

STAT:

Signal transducer and activator of transcription

T2D:

Type 2 diabetes

t-SNARE:

Target membrane SNARE protein

Tyk-2:

Tyrosine kinase-2

VAMP2:

Vesicle-associated membrane SNARE protein-2

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Acknowledgments

We would first like to express our regret to whose work was not cited due to lack of space. We would like to Dr. Stephanie Yoder and Dr. Michael Kalwat for the critical reading of the manuscript. This study was supported by grants from the National Institutes of Health (DK067912 and DK076614 to D.C.T.), the Indiana University School of Medicine Showalter Foundation (to E.O.), and a pre-doctoral fellowship from the American Heart Association (to L.R.).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    Latha Ramalingam

  2. Department of Pediatrics, Herman B Wells Center, Indiana University School of Medicine, Indianapolis, IN, USA

    Eunjin Oh

  3. Departments of Pediatrics, Biochemistry and Molecular Biology, and Cellular and Integrative Physiology, Herman B Wells Center, Indiana University School of Medicine, 635 Barnhill Drive MS 2031, Indianapolis, IN, 46202, USA

    Debbie C. Thurmond

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  1. Latha Ramalingam
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  2. Eunjin Oh
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  3. Debbie C. Thurmond
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Correspondence to Debbie C. Thurmond.

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Ramalingam, L., Oh, E. & Thurmond, D.C. Novel roles for insulin receptor (IR) in adipocytes and skeletal muscle cells via new and unexpected substrates. Cell. Mol. Life Sci. 70, 2815–2834 (2013). https://doi.org/10.1007/s00018-012-1176-1

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  • DOI: https://doi.org/10.1007/s00018-012-1176-1

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