The protein tyrosine phosphatase alpha modifies insulin secretion in INS-1E cells.
ABSTRACT Increasing evidence indicates a role of insulin signalling for insulin secretion from the pancreatic beta-cells. Therefore, regulators of insulin signalling, like protein tyrosine phosphatases, could also have an impact on insulin secretion. Here, we investigated a possible role of the negative regulator protein tyrosine phosphatase alpha (PTP alpha) for insulin secretion. RT-PCR analysis confirmed that both splice variants of the extracellular domain of PTP alpha that vary by an insert of 9 amino acids are expressed in human islets and insulinoma cells (INS-1E, RIN1046-38). Overexpression of the wild type PTP alpha splice variant containing the 9 amino acids reduced insulin secretion, as did a mutant form unable to bind Grb2 (Tyr798Phe). By contrast, overexpression of a phosphatase inactive mutant improved insulin secretion. These data reveal a functional relevance of PTP alpha for insulin secretion.
- SourceAvailable from: Elaine Xu[Show abstract] [Hide abstract]
ABSTRACT: Insulin resistance is a major disorder that links obesity to type 2 diabetes mellitus (T2D). It involves defects in the insulin actions owing to a reduced ability of insulin to trigger key signaling pathways in major metabolic tissues. The pathogenesis of insulin resistance involves several inhibitory molecules that interfere with the tyrosine phosphorylation of the insulin receptor and its downstream effectors. Among those, growing interest has been developed toward the protein tyrosine phosphatases (PTPs), a large family of enzymes that can inactivate crucial signaling effectors in the insulin signaling cascade by dephosphorylating their tyrosine residues. Herein we briefly review the role of several PTPs that have been shown to be implicated in the regulation of insulin action, and then focus on the Src homology 2 (SH2) domain-containing SHP1 and SHP2 enzymes, since recent reports have indicated major roles for these PTPs in the control of insulin action and glucose metabolism. Finally, the therapeutic potential of targeting PTPs for combating insulin resistance and alleviating T2D will be discussed.Reviews in Endocrine and Metabolic Disorders 11/2013; 15(1). · 4.58 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: We have identified the PTP Receptor-Type IV (PTPR4) family, including one form of PTPα and two forms of PTPε (PTPε M and PTPε C) in flounder. The existence of PTPε C was the first report in non-mammalian animals. Semi-quantitative RT-PCR showed independent expression patterns of the three forms. The sequence of PTPε C was identical to that of PTPε M except for its 5'-terminal regions. Southern blot analysis proved that there existed only one PTPε gene in the genome, indicating that the two isoforms of PTPε might have been derived from alternative splicing of this gene. Phylogenetic analysis also provided evidence that the gene duplication from the ancestor gene to PTPα and PTPε occurred before the divergence of Gnathastomata and Agnatha. These results showed that the functional evolution of protein phosphorylation is promoted by not only genome duplication, but also elaborate regulation of expression. INTRODUCTION Tyrosine phosphorylation, controlled by the coordinated actions of protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs), is a critical mechanism for the regulation of numerous cell functions (Tonks and Neel, 1996; Mustelin et al., 2002). Since the first identification, PTP members have been identified in many organisms (Tonks et al., 1988; Fischer et al., 1991; Alonso et al., 2004). PTPR4 contain two cytoplasmic PTP domains (D1 and D2), one transmembrane segment and an extracellular domain. PTPα and PTPε are the only known members of PTPR4 (Sap et al., 1990; Matthews et al., 1990). The precise subcellular localization of PTPs is an important for regulating their physiological roles (Mauro and Dixon, 1994; Fischer, 1999). PTPε includes four forms of proteins coded by a single PTPε gene. The two most prevalent forms are the transmembrane form (PTPε M) and cytoplasmic form (PTPε C) derived from alternatively splicing of PTPε gene (Elson and Leder, 1995b; Elson et al., 1996). The other two forms p67 PTPε and p65 PTPε are produced by initiation of translation of PTPε mRNA, and specific proteolytic cleavage of larger PTPε proteins, respectively (Gil-Henn et al., 2001; Kraut et al., 2002). Each form possesses unique expression patterns, subcellular localizations, and functions. In teleost fish, Okubo and Aida (2003) isolated and characterized PTPα and PTPε M in medaka, and demonstrated that GnRH down regulates their expression. Van der Sar et al (2001) cloned PTPα and PTPε M in zebrafish and described their expression during development. However, none of cytoplasmic form of PTPε was identified in teleost fish. Here we report the cDNAs of PTPα and two forms of PTPε, from Japanese flounder. We proved that these two isoforms of PTPε are also from one PTPε gene by alternative mRNA splicing. The unique expression of PTPα and two isoforms of PTPε mRNAs in various tissues are described.Genes & Genetic Systems - GENES GENET SYST. 01/2008; 83(2).
- [Show abstract] [Hide abstract]
ABSTRACT: This study was undertaken to identify genetic polymorphisms that are associated with the risk of an elevated fasting glucose (FG) level using genome-wide analyses. We explored a quantitative trait locus (QTL) for FG level in a genome-wide study from a Korean twin-family cohort (the Healthy Twin Study) using a combined linkage and family-based association analysis approach. We investigated 1,754 individuals, which included 432 families and 219 pairs of monozygotic twins. Regions of chromosomes 2q23.3-2q31.1, 15q26.1-15q26.3, 16p12.1, and 20p13-20p12.2, were found to show evidence of linkage with FG level, and several markers in these regions were found to be significantly associated with FG level using family-based or general association tests. In particular, a single-nucleotide polymorphism (rs6138953) on the PTPRA gene in the 20p13 region (combined P = 1.8 × 10(-6)) was found to be associated with FG level, and the PRKCB1 gene (in 16p12.1) to be possibly associated with FG level. In conclusion, multiple regions of chromosomes 2q23.3-2q31.1, 15q26.1-15q26.3, 16p12.1, and 20p13-20p12.2 are associated with FG level in our Korean twin-family cohort. The combined approach of genome-wide linkage and family-based association analysis is useful to identify novel or known genetic regions concerning FG level in a family cohort study.Journal of Korean medical science 03/2013; 28(3):415-23. · 0.84 Impact Factor