Tyrosine Phosphorylation of Tub and Its Association with Src Homology 2 Domain-containing Proteins Implicate Tub in Intracellular Signaling by Insulin

Kapeller, Rosana; Moriarty, Ann; Strauss, Ann; Stubdal, Hilde; Theriault, Kelly; Siebert, Elizabeth; Chickering, Troy W.; Morgenstern, Jay P.; Tartaglia, Louis A.; Lillie, James W.

doi:10.1074/jbc.274.35.24980

Cited by 87 publications

(47 citation statements)

References 43 publications

(43 reference statements)

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“…21 The tubby mouse has a naturally occurring mutation in the tub gene and is characterized by hyperphagia and obesity (as well as visual and hearing deficits). Importantly, targeted deletion of tub results in an apparently identical phenotype, suggesting that the tubby mouse has a loss-of-function mutation.…”

Section: Insulin Within the Brainmentioning

confidence: 99%

Insulin as an adiposity signal

Woods

Seeley

2001

Int J Obes

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Insulin is now well established as an adiposity signal that acts in the brain to influence energy homeostasis. It is secreted in direct proportion to adiposity; it enters the brain from the blood, and it interacts with neurons in the ventral hypothalamus. Experimental manipulation of brain insulin causes predictable changes of food intake and body weight. Because insulin shares many properties with other adiposity signals, especially leptin, in this regard, it is important to recognize the similarities and differences in the signal each conveys to the brain in order to design effective therapeutic approaches to treat pathologies of eating and body weight.

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Section: Insulin Within the Brainmentioning

confidence: 99%

Insulin as an adiposity signal

Woods

Seeley

2001

Int J Obes

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“…Cell culture studies and the determination of the crystal structure of the conserved C-terminal domain of TUB have resulted in the proposal that TUB may respond to signals from G proteins to activate translocation from the plasma membrane to the nucleus where it might function as a novel transcription factor (Boggon et al, 1999;Santagata et al, 2001). Other proposed functions for TULP proteins include involvement in intracellular insulin signaling and vesicular trafficking (Hagstrom et al, 1999;Hagstrom et al, 2001;Kapeller et al, 1999). Although the precise function of TULP proteins is unknown, two of the proteins have been linked to photoreceptor degeneration, namely TUB and TULP1.…”

Section: Introductionmentioning

confidence: 99%

Mutation screen of the TUB gene in patients with retinitis pigmentosa and Leber congenital amaurosis

Pauer

Traboulsi

et al. 2006

Experimental Eye Research

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TUB is the first identified member of the TULP family of four proteins with unknown function. A spontaneous mutation in murine tub causes retinal degeneration, obesity, and deafness. Mutations in another member of the TULP family, TULP1, are a cause of autosomal recessive retinitis pigmentosa (RP). These findings prompted us to investigate TUB as a candidate gene for RP and Leber congenital amaurosis (LCA). A mutation screen of the entire coding region of the TUB gene in 159 unrelated patients with autosomal recessive RP, 114 unrelated patients with simplex RP, and 21 unrelated patients with LCA uncovered 18 sequence variations. Of these, seven were missense mutations, six were isocoding changes, and five were intronic polymorphisms. All seven missense mutations were identified as heterozygous changes and no defect could be found in the other allele. None of the isocoding variants or intronic polymorphisms are predicted to create or destroy splice donor or acceptor sites based on splice-site prediction software. Although variant alleles of the TUB gene were found, none could be definitively associated with a specific retinal disease.

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“…Tyrosine 221 phosphorylation by c-Abl results in CrkII inactivation because of intramolecular folding caused by the interaction of the Crk SH2 domain with phosphotyrosine 221 (24). Although the c-Abl role in IR signaling is not known, there is evidence indicating that c-Abl and IR may share common substrates, including the Tub and SORBS1 adapter proteins (25,26). In particular, Tub is phosphorylated by both IR and c-Abl, whereas SORBS1 may interact with both IR and c-Abl, and this association is insulin-dependent.…”

Section: Insulin and Igf-i Receptors (Ir And Igf-ir)mentioning

confidence: 99%

Role of c-Abl in Directing Metabolic versus Mitogenic Effects in Insulin Receptor Signaling

Frasca

Pandini

Malaguarnera

et al. 2007

Journal of Biological Chemistry

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Insulin and IGF-I receptors (IR and IGF-IR) 3 are heterotetrameric oligomers sharing a high degree of homology. They consist of two extracellular 135-kDa ␣ subunits that contain the ligand domain and two 95-kDa transmembrane ␤ subunits endowed of tyrosine kinase activity (1, 2). Insulin and IGF-I binding to the receptor ␣ subunits stimulates autophosphorylation of the receptor cytoplasmic ␤ tail at multiple tyrosine residues. Activated ␤ subunits interact with and phosphorylate several intracellular substrates at tyrosine residues, including the IRS family proteins (IRS-1/2/3/4) and Gab1 (1, 2). These tyrosine-phosphorylated substrates provide docking sites for SH2-contanining proteins, including p85, the regulatory subunits of phosphatidylinositol 3-kinase, and Grb2, a small adapter protein involved in the activation of the Ras pathway (1-3). Activation of the phosphatidylinositol 3-kinase pathway stimulates Akt and, as a consequence, elicits metabolic effects. On the other hand, the recruitment of Grb2 results in the activation of the Ras/ERK pathway, which in turn regulates cell proliferation and differentiation (1-3).Despite the high similarity between IR and IGF-IR, these two receptors display different effects: IR mainly elicits metabolic effects, including glucose uptake and glycogen synthesis, and IGF-IR mainly stimulates cell proliferation, survival, and differentiation. The mechanisms underlying the different actions of IR and IGF-IR have been extensively studied and are believed to depend on the preferential recruitment and activation of different intracellular substrates, including CrkII, Grb10, 14-3-3, and the focal adhesion kinase (FAK) (1-3).The FAK is an ubiquitously expressed cytoplasmic tyrosine kinase, involved in integrin and growth factor receptor signaling. It is widely accepted that FAK is a point of convergence in the actions of the extracellular matrix and growth factors (4). FAK tyrosine phosphorylation occurs rapidly in response to growth factor stimulation including PDGF, epidermal growth factor, and IGF-I (4, 5). In particular, FAK phosphorylation at tyrosine 925 creates a binding site for the SH2 domain of Grb2, thereby activating the Ras/ERK pathway (6). Moreover, the activated FAK phosphorylates several adapter proteins including the p130 CAS (7) and paxillin (8), which in turn provide docking sites to the small SH2-containing proteins Crk and Nck (7, 9, 10). Similarly to Grb2, also Crk and Nck recruitment results in the activation of the Ras/ERK pathway (4). Because FAK is able to trigger the Ras pathway in response to several stimuli, it has been proposed that FAK plays a major role in mediating the effect of tyrosine kinase receptors on the ERK activation. Evidence supporting this hypothesis was obtained in FAK Ϫ/Ϫ cells, which exhibit a defect in ERK activation in response to serum and PDGF stimulation (11). Moreover, in NIH3T3 fibroblasts the overexpression of a dominant negative FAK blocks seruminduced activation of ERK (12). At variance with most growth factors, which sti...

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Tyrosine Phosphorylation of Tub and Its Association with Src Homology 2 Domain-containing Proteins Implicate Tub in Intracellular Signaling by Insulin

Cited by 87 publications

References 43 publications

Insulin as an adiposity signal

Insulin as an adiposity signal

Mutation screen of the TUB gene in patients with retinitis pigmentosa and Leber congenital amaurosis

Role of c-Abl in Directing Metabolic versus Mitogenic Effects in Insulin Receptor Signaling

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