Insulin Receptor Substrate 2 (IRS2)-Deficient Mice Show Sensorineural Hearing Loss That Is Delayed by Concomitant Protein Tyrosine Phosphatase 1B (PTP1B) Loss of Function

The high activity of the insulin-signaling pathway contributes to the enhanced feeding-induced stimulation of translation initiation in skeletal muscle of neonatal pigs. Protein-tyrosine-phosphatase 1B (PTP1B) is a negative regulator of the tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrate 1 (IRS-1). The activity of PTP1B is determined mainly by its association with IR and Grb2. We examined the level of PTP1B activity, PTP1B protein abundance, PTP1B tyrosine phosphorylation, and the association of PTP1B with IR and Grb2 in skeletal muscle and liver of fasted and fed 7- and 26-day-old pigs. PTP1B activity in skeletal muscle was lower (P < 0.05) in 7- compared with 26-day-old pigs but in liver was similar in the two age groups. PTP1B abundances were similar in muscle but lower (P < 0.05) in liver of 7- compared with 26-day-old pigs. PTP1B tyrosine phosphorylation in muscle was lower (P < 0.05) in 7- than in 26-day-old pigs. The associations of PTP1B with IR and with Grb2 were lower (P < 0.05) at 7 than at 26 days of age in muscle, but there were no age effects in liver. Finally, in both age groups, fasting did not have any effect on these parameters. These results indicate that basal PTP1B activation is developmentally regulated in skeletal muscle of neonatal pigs, consistent with the developmental changes in the activation of the insulin-signaling pathway reported previously. Reduced PTP1B activation in neonatal muscle likely contributes to the enhanced insulin sensitivity of skeletal muscle in neonatal pigs.

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Molecular Basis for the Dephosphorylation of the Activation Segment of the Insulin Receptor by Protein Tyrosine Phosphatase 1B

Molecular Cell ◽

10.1016/s1097-2765(00)00137-4 ◽

2000 ◽

Vol 6 (6) ◽

pp. 1401-1412 ◽

Cited By ~ 293

Author(s):

Annette Salmeen ◽

Jannik N Andersen ◽

Michael P Myers ◽

Nicholas K Tonks ◽

David Barford

Keyword(s):

Insulin Receptor ◽

Protein Tyrosine Phosphatase ◽

Molecular Basis ◽

Tyrosine Phosphatase ◽

Protein Tyrosine Phosphatase 1B ◽

Protein Tyrosine ◽

Activation Segment

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Autosomal Recessive Congenital Sensorineural Hearing Loss due to a Novel Compound Heterozygous PTPRQ Mutation in a Chinese Family

Neural Plasticity ◽

10.1155/2018/9425725 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Xia Wu ◽

Shan Wang ◽

Sen Chen ◽

Ying-ying Wen ◽

Bo Liu ◽

...

Keyword(s):

Hearing Loss ◽

Sensorineural Hearing Loss ◽

Tyrosine Phosphatase ◽

Sensorineural Hearing ◽

Paternal Allele ◽

Chinese Family ◽

Compound Heterozygous ◽

Gene Encoding ◽

Sequencing Method ◽

And Function

PTPRQ gene, encoding protein tyrosine phosphatase receptor Q, is essential for the normal maturation and function of hair bundle in the cochlea. Its mutations can cause the defects of stereocilia in hair cell, which lead to nonsyndromic sensorineural hearing loss. Using next-generation sequencing and Sanger sequencing method, we identified a novel compound heterozygous missense mutation, c.4472C>T p.T1491M (maternal allele) and c.1973T>C p.V658A (paternal allele), in PTPRQ gene. The two mutations are the first reported to be the cause of recessively inherited sensorineural hearing loss. Hearing loss levels and progression involved by PTPRQ mutations among the existing cases seem to be varied, and the relationship between genotypes and phenotypes is unclear. Our data here further prove the important role of PTPRQ in auditory function and provide more information for the further mechanism research of PTPRQ-related hearing loss.

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C1-Ten Is a Protein Tyrosine Phosphatase of Insulin Receptor Substrate 1 (IRS-1), Regulating IRS-1 Stability and Muscle Atrophy

Molecular and Cellular Biology ◽

10.1128/mcb.01447-12 ◽

2013 ◽

Vol 33 (8) ◽

pp. 1608-1620 ◽

Cited By ~ 19

Author(s):

A. Koh ◽

M. N. Lee ◽

Y. R. Yang ◽

H. Jeong ◽

J. Ghim ◽

...

Keyword(s):

Insulin Receptor ◽

Muscle Atrophy ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Insulin Receptor Substrate ◽

Insulin Receptor Substrate 1 ◽

Protein Tyrosine

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Adapter Function of Protein-tyrosine Phosphatase 1D in Insulin Receptor/Insulin Receptor Substrate-1 Interaction

Journal of Biological Chemistry ◽

10.1074/jbc.270.49.29189 ◽

1995 ◽

Vol 270 (49) ◽

pp. 29189-29193 ◽

Cited By ~ 45

Author(s):

Alexei Kharitonenkov ◽

Jürgen Schnekenburger ◽

Zhengjun Chen ◽

Pjotr Knyazev ◽

Suhad Ali ◽

...

Keyword(s):

Insulin Receptor ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Insulin Receptor Substrate ◽

Insulin Receptor Substrate 1 ◽

Protein Tyrosine

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Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice

Molecular and Cellular Biology ◽

10.1128/mcb.20.15.5479-5489.2000 ◽

2000 ◽

Vol 20 (15) ◽

pp. 5479-5489 ◽

Cited By ~ 894

Author(s):

Lori D. Klaman ◽

Olivier Boss ◽

Odile D. Peroni ◽

Jason K. Kim ◽

Jennifer L. Martino ◽

...

Keyword(s):

Insulin Sensitivity ◽

Energy Expenditure ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Protein Tyrosine Phosphatase 1B ◽

Tissue Specific ◽

Protein Tyrosine ◽

Ptp 1B ◽

Deficient Mice

ABSTRACT Protein-tyrosine phosphatase 1B (PTP-1B) is a major protein-tyrosine phosphatase that has been implicated in the regulation of insulin action, as well as in other signal transduction pathways. To investigate the role of PTP-1B in vivo, we generated homozygotic PTP-1B-null mice by targeted gene disruption. PTP-1B-deficient mice have remarkably low adiposity and are protected from diet-induced obesity. Decreased adiposity is due to a marked reduction in fat cell mass without a decrease in adipocyte number. Leanness in PTP-1B-deficient mice is accompanied by increased basal metabolic rate and total energy expenditure, without marked alteration of uncoupling protein mRNA expression. In addition, insulin-stimulated whole-body glucose disposal is enhanced significantly in PTP-1B-deficient animals, as shown by hyperinsulinemic-euglycemic clamp studies. Remarkably, increased insulin sensitivity in PTP-1B-deficient mice is tissue specific, as insulin-stimulated glucose uptake is elevated in skeletal muscle, whereas adipose tissue is unaffected. Our results identify PTP-1B as a major regulator of energy balance, insulin sensitivity, and body fat stores in vivo.

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