TBC1D4

{{Short description|Protein-coding gene in the species Homo sapiens}}

AS160 (Akt substrate of 160 kDa), which was originally known as TBC1 domain family member 4 (TBC1D4),{{cite journal | vauthors = Sakamoto K, Holman GD | title = Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 295 | issue = 1 | pages = E29–E37 | date = July 2008 | pmid = 18477703 | pmc = 2493596 | doi = 10.1152/ajpendo.90331.2008 }} is a Rab GTPase-activating protein that in humans is encoded by the TBC1D4 gene.{{cite journal | vauthors = Kurihara LJ, Semenova E, Miller W, Ingram RS, Guan XJ, Tilghman SM | title = Candidate genes required for embryonic development: a comparative analysis of distal mouse chromosome 14 and human chromosome 13q22 | journal = Genomics | volume = 79 | issue = 2 | pages = 154–161 | date = February 2002 | pmid = 11829485 | doi = 10.1006/geno.2002.6692 | citeseerx = 10.1.1.16.1099 }}{{cite journal | vauthors = Kane S, Sano H, Liu SC, Asara JM, Lane WS, Garner CC, Lienhard GE | title = A method to identify serine kinase substrates. Akt phosphorylates a novel adipocyte protein with a Rab GTPase-activating protein (GAP) domain | journal = The Journal of Biological Chemistry | volume = 277 | issue = 25 | pages = 22115–22118 | date = June 2002 | pmid = 11994271 | doi = 10.1074/jbc.C200198200 | doi-access = free }}{{cite journal | vauthors = Matsumoto Y, Imai Y, Lu Yoshida N, Sugita Y, Tanaka T, Tsujimoto G, Saito H, Oshida T | title = Upregulation of the transcript level of GTPase activating protein KIAA0603 in T cells from patients with atopic dermatitis | journal = FEBS Letters | volume = 572 | issue = 1–3 | pages = 135–140 | date = August 2004 | pmid = 15304337 | doi = 10.1016/j.febslet.2004.07.023 | doi-access = free | bibcode = 2004FEBSL.572..135M }}{{cite web | title = Entrez Gene: TBC1D4 TBC1 domain family, member 4| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9882}}

The 160 kD protein product was first discovered in a screen for novel substrates of the serine-threonine kinase Akt2, which phosphorylates AS160 at Thr-642 and Ser-588{{cite journal | vauthors = Sano H, Kane S, Sano E, Mîinea CP, Asara JM, Lane WS, Garner CW, Lienhard GE | title = Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation | journal = The Journal of Biological Chemistry | volume = 278 | issue = 17 | pages = 14599–14602 | date = April 2003 | pmid = 12637568 | doi = 10.1074/jbc.C300063200 | doi-access = free }} after insulin stimulation.{{cite journal | vauthors = Kane S, Sano H, Liu SC, Asara JM, Lane WS, Garner CC, Lienhard GE | title = A method to identify serine kinase substrates. Akt phosphorylates a novel adipocyte protein with a Rab GTPase-activating protein (GAP) domain | journal = The Journal of Biological Chemistry | volume = 277 | issue = 25 | pages = 22115–22118 | date = June 2002 | pmid = 11994271 | doi = 10.1074/jbc.C200198200 | doi-access = free }} Insulin stimulation of fat and muscle cells results in translocation of the glucose transporter GLUT4 to the plasma membrane, and this translocation process is dependent on phosphorylation of AS160.{{cite journal | vauthors = Sano H, Kane S, Sano E, Mîinea CP, Asara JM, Lane WS, Garner CW, Lienhard GE | title = Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation | journal = The Journal of Biological Chemistry | volume = 278 | issue = 17 | pages = 14599–14602 | date = April 2003 | pmid = 12637568 | doi = 10.1074/jbc.C300063200 | doi-access = free }} The role of AS160 in GLUT4 translocation is mediated by its GTPase activating domain and interactions with Rab proteins in vesicle formation, increasing GLUT4 translocation when its GTPase activity is inhibited by Akt phosphorylation. Specifically, this inhibition activates RAB2A, RAB8A, RAB10 and RAB14.{{cite journal | vauthors = Mîinea CP, Sano H, Kane S, Sano E, Fukuda M, Peränen J, Lane WS, Lienhard GE | title = AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain | journal = The Biochemical Journal | volume = 391 | issue = Pt 1 | pages = 87–93 | date = October 2005 | pmid = 15971998 | pmc = 1237142 | doi = 10.1042/BJ20050887 }}

AS160 also contains a calmodulin-binding domain, and this domain mediates phosphorylation-independent glucose uptake in muscle cells.{{cite journal | vauthors = Kramer HF, Taylor EB, Witczak CA, Fujii N, Hirshman MF, Goodyear LJ | title = Calmodulin-binding domain of AS160 regulates contraction- but not insulin-stimulated glucose uptake in skeletal muscle | journal = Diabetes | volume = 56 | issue = 12 | pages = 2854–2862 | date = December 2007 | pmid = 17717281 | doi = 10.2337/db07-0681 | doi-access = free }}

Isoforms

The TBC1D4 gene has two isoforms - a long isoform expressed almost exclusively in skeletal and cardiac muscle, and a short isoform with more widespread expression.{{cite journal | vauthors = Moltke I, Grarup N, Jørgensen ME, Bjerregaard P, Treebak JT, Fumagalli M, Korneliussen TS, Andersen MA, Nielsen TS, Krarup NT, Gjesing AP, Zierath JR, Linneberg A, Wu X, Sun G, Jin X, Al-Aama J, Wang J, Borch-Johnsen K, Pedersen O, Nielsen R, Albrechtsen A, Hansen T | title = A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes | journal = Nature | volume = 512 | issue = 7513 | pages = 190–193 | date = August 2014 | pmid = 25043022 | doi = 10.1038/nature13425 | bibcode = 2014Natur.512..190M }}

Pathogenic mutations

A nonsense p.Arg684Ter variant in the TBC1D4 gene has been identified in the Greenlandic Inuit population that is associated with increased risk of type II diabetes. The variant mainly affects individuals with two copies of the mutation, indicating recessive inheritance. Although the mutation does not effect the short isoform of the protein, it introduces a premature stop codon in the long isoform, resulting in the absence of the long isoform protein in muscle tissue.

Homozygous carriers of the p.Arg684Ter allele have lower concentrations of fasting plasma glucose and insulin. They also have a markedly increased risk of Type II Diabetes — individuals with two mutant genes have about 10 times the chance of contracting Type II diabetes (odds ratio = 10.3) compared to noncarriers. Approximately 3.8% of Greenlanders are homozygous for the mutation, which is estimated to be responsible for approximately 10% of Type II Diabetes cases in Greenland.

TBC1D4

Isoforms

Pathogenic mutations

References

Further reading