Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic

Kei Sakamoto, Geoffrey D. Holman

    Research output: Contribution to journalArticle

    277 Citations (Scopus)

    Abstract

    Vesicular traffic of the glucose transporter GLUT4 occurs in response to insulin, muscle contraction, and metabolic stimuli that lead to changes in the energy status of the cell. These stimuli are associated with linked kinase cascades that lead to changes in glucose uptake that meet the energy challenges imposed on the highly regulated cell types in insulin-responsive tissues. The need to mechanistically link these kinase-associated stimuli to identifiable intermediates in vesicular traffic has long been known but has been difficult to fulfill. The Rab-GTPase-activating proteins AS160 and TBC1D1 have now emerged as strong candidates to fill this void. Here we review the initial discovery of these proteins as phosphorylated substrates for Akt and the more recent emerging data that indicate that these proteins are substrates for additional kinases that are downstream of contraction and energy status signaling. The mechanism of coupling these phosphorylated proteins to vesicle traffic appears to be dependent on linking to small GTPase of the Rab family. We examine the current state of a hypothesis that suggests that phosphorylation of the Rab-GTPase-activating proteins leads to increased GTP loading of Rab proteins on GLUT4 vesicles and subsequently to increased interaction with Rab effectors that control GLUT4 vesicle translocation.
    Original languageEnglish
    Pages (from-to)E29-E37
    JournalAmerican Journal of Physiology, Endocrinology and Metabolism
    Volume295
    Issue number1
    DOIs
    Publication statusPublished - 2008

    Fingerprint

    rab GTP-Binding Proteins
    GTPase-Activating Proteins
    Phosphotransferases
    Glucose Transporter Type 4
    Insulin
    Proteins
    Monomeric GTP-Binding Proteins
    Facilitative Glucose Transport Proteins
    Muscle Contraction
    Guanosine Triphosphate
    Phosphorylation
    Glucose

    Keywords

    • Animals
    • Diabetes Mellitus, Type 2
    • GTPase-Activating Proteins
    • Glucose Transporter Type 4
    • Humans
    • Insulin
    • Muscle Contraction
    • Muscle, Skeletal
    • Phosphorylation
    • Proto-Oncogene Proteins c-akt

    Cite this

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    title = "Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic",
    abstract = "Vesicular traffic of the glucose transporter GLUT4 occurs in response to insulin, muscle contraction, and metabolic stimuli that lead to changes in the energy status of the cell. These stimuli are associated with linked kinase cascades that lead to changes in glucose uptake that meet the energy challenges imposed on the highly regulated cell types in insulin-responsive tissues. The need to mechanistically link these kinase-associated stimuli to identifiable intermediates in vesicular traffic has long been known but has been difficult to fulfill. The Rab-GTPase-activating proteins AS160 and TBC1D1 have now emerged as strong candidates to fill this void. Here we review the initial discovery of these proteins as phosphorylated substrates for Akt and the more recent emerging data that indicate that these proteins are substrates for additional kinases that are downstream of contraction and energy status signaling. The mechanism of coupling these phosphorylated proteins to vesicle traffic appears to be dependent on linking to small GTPase of the Rab family. We examine the current state of a hypothesis that suggests that phosphorylation of the Rab-GTPase-activating proteins leads to increased GTP loading of Rab proteins on GLUT4 vesicles and subsequently to increased interaction with Rab effectors that control GLUT4 vesicle translocation.",
    keywords = "Animals, Diabetes Mellitus, Type 2, GTPase-Activating Proteins, Glucose Transporter Type 4, Humans, Insulin, Muscle Contraction, Muscle, Skeletal, Phosphorylation, Proto-Oncogene Proteins c-akt",
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    Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic. / Sakamoto, Kei; Holman, Geoffrey D.

    In: American Journal of Physiology, Endocrinology and Metabolism, Vol. 295, No. 1, 2008, p. E29-E37.

    Research output: Contribution to journalArticle

    TY - JOUR

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    AU - Holman, Geoffrey D.

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    N2 - Vesicular traffic of the glucose transporter GLUT4 occurs in response to insulin, muscle contraction, and metabolic stimuli that lead to changes in the energy status of the cell. These stimuli are associated with linked kinase cascades that lead to changes in glucose uptake that meet the energy challenges imposed on the highly regulated cell types in insulin-responsive tissues. The need to mechanistically link these kinase-associated stimuli to identifiable intermediates in vesicular traffic has long been known but has been difficult to fulfill. The Rab-GTPase-activating proteins AS160 and TBC1D1 have now emerged as strong candidates to fill this void. Here we review the initial discovery of these proteins as phosphorylated substrates for Akt and the more recent emerging data that indicate that these proteins are substrates for additional kinases that are downstream of contraction and energy status signaling. The mechanism of coupling these phosphorylated proteins to vesicle traffic appears to be dependent on linking to small GTPase of the Rab family. We examine the current state of a hypothesis that suggests that phosphorylation of the Rab-GTPase-activating proteins leads to increased GTP loading of Rab proteins on GLUT4 vesicles and subsequently to increased interaction with Rab effectors that control GLUT4 vesicle translocation.

    AB - Vesicular traffic of the glucose transporter GLUT4 occurs in response to insulin, muscle contraction, and metabolic stimuli that lead to changes in the energy status of the cell. These stimuli are associated with linked kinase cascades that lead to changes in glucose uptake that meet the energy challenges imposed on the highly regulated cell types in insulin-responsive tissues. The need to mechanistically link these kinase-associated stimuli to identifiable intermediates in vesicular traffic has long been known but has been difficult to fulfill. The Rab-GTPase-activating proteins AS160 and TBC1D1 have now emerged as strong candidates to fill this void. Here we review the initial discovery of these proteins as phosphorylated substrates for Akt and the more recent emerging data that indicate that these proteins are substrates for additional kinases that are downstream of contraction and energy status signaling. The mechanism of coupling these phosphorylated proteins to vesicle traffic appears to be dependent on linking to small GTPase of the Rab family. We examine the current state of a hypothesis that suggests that phosphorylation of the Rab-GTPase-activating proteins leads to increased GTP loading of Rab proteins on GLUT4 vesicles and subsequently to increased interaction with Rab effectors that control GLUT4 vesicle translocation.

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    KW - Diabetes Mellitus, Type 2

    KW - GTPase-Activating Proteins

    KW - Glucose Transporter Type 4

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    KW - Insulin

    KW - Muscle Contraction

    KW - Muscle, Skeletal

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    KW - Proto-Oncogene Proteins c-akt

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