80K-H Acts as a Signaling Bridge in Intact Living Cells Between PKCζ and the GLUT4 Translocation Regulator Munc18c

Smithers, Natalie P.; Hodgkinson, Conrad P.; Cuttle, Matt; Sale, Graham J.

doi:10.1080/10799890802598571

Cited by 4 publications

(3 citation statements)

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“…80K-H has been associated with the regulation of intracellular signaling downstream of both the fibroblast growth factor receptor [68,69] and the advanced glycosylation end products receptor [70], and it participates in the regulation of protein translocation [71]. 80K-H interacts with PKCζ and munc18c to induce glucose transporter 4 translocation to the plasma membrane [72]. A recent study suggests that 80K-H can regulate IP 3 -induced calcium release by interacting with the cytoplasmic tail of IP 3 -receptors [73].…”

Section: Discussionmentioning

confidence: 99%

Identification of calcium-binding proteins associated with the human sperm plasma membrane

Naaby-Hansen

Diekman

Shetty

et al. 2010

Reprod Biol Endocrinol

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BackgroundThe precise composition of the human sperm plasma membrane, the molecular interactions that define domain specific functions, and the regulation of membrane associated proteins during the capacitation process, still remain to be fully understood. Here, we investigated the repertoire of calcium-regulated proteins associated with the human sperm plasma membrane.MethodsSurface specific radioiodination was combined with two-dimensional gel electrophoresis, a 45Ca-overlay assay, computer assisted image analysis and mass spectrometry to identify calcium-binding proteins exposed on the human sperm surface.ResultsNine acidic 45Ca-binding sperm proteins were excised from stained preparative 2D gels and identified by mass spectrometry. Five of the calcium binding proteins; HSPA2 (HSP70-1), HSPA5 (Bip), HYOU1 (ORP150), serum amyloid P-component (SAP) and protein kinase C substrate 80K-H (80K-H) were found to be accessible to Iodo-Bead catalyzed 125I-labelling on the surface of intact human sperm. Agglutination and immunofluorescence analysis confirmed that SAP is situated on the plasma membrane of intact, motile sperm as well as permeabilized cells. Western blot analysis showed increased phosphorylation of human sperm 80K-H protein following in vitro capacitation. This is the first demonstration of the 80K-H protein in a mammalian sperm.ConclusionThe presence of SAP on the surface of mature sperm implies that SAP has a physiological role in reproduction, which is thought to be in the removal of spermatozoa from the female genital tract via phagocytosis. Since 80K-H is a Ca2+-sensor recently implicated in the regulation of both inositol 1,4,5-trisphosphate receptor and transient receptor potential (TRP) cation channel activities, its detection in sperm represents the first direct signaling link between PKC and store-operated calcium channels identified in human sperm.

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Section: Discussionmentioning

confidence: 99%

Identification of calcium-binding proteins associated with the human sperm plasma membrane

Naaby-Hansen

Diekman

Shetty

et al. 2010

Reprod Biol Endocrinol

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“…The 80K-H protein (80 kDa) was originally identified as a PKC binding partner and is widely expressed, especially at the plasma membrane of insulin-sensitive 3T3L1 adipocytes and L6 myotubes (47). 80K-H has been implicated in vesicle trafficking events via a close relationship to the protein VASAP-60 (13), as well as in GLUT4 vesicle transport through its ability to interact with both Munc18c and PKC in an insulin-dependent manner (47,119). The requirement of 80K-H in glucose uptake in vivo and/or primary cells and its putative role as a signaling link between PKC and Munc18c await further investigation.…”

Section: Munc18-syntaxin Complexes: Molecular Mechanismsmentioning

confidence: 99%

Exocytosis mechanisms underlying insulin release and glucose uptake: conserved roles for Munc18c and syntaxin 4

Jewell

Thurmond

2010

American Journal of Physiology-Regulatory, Integrative and Comp

106

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Type 2 diabetes has been coined "a two-hit disease," as it involves specific defects of glucose-stimulated insulin secretion from the pancreatic beta cells in addition to defects in peripheral tissue insulin action required for glucose uptake. Both of these processes, insulin secretion and glucose uptake, are mediated by SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein core complexes composed of syntaxin, SNAP-23/25, and VAMP proteins. The SNARE core complex is regulated by the Sec1/Munc18 (SM) family of proteins, which selectively bind to their cognate syntaxin isoforms with high affinity. The process of insulin secretion uses multiple Munc18-syntaxin isoform pairs, whereas insulin action in the peripheral tissues appears to use only the Munc18c-syntaxin 4 pair. Importantly, recent reports have linked obesity and Type 2 diabetes in humans with changes in protein levels and single nucleotide polymorphisms (SNPs) of Munc18 and syntaxin isoforms relevant to these exocytotic processes, although the molecular mechanisms underlying the observed phenotypes remain incomplete (5, 104, 144). Given the conservation of these proteins in two seemingly disparate processes and the need to design and implement novel and more effective clinical interventions, it will be vitally important to delineate the mechanisms governing these conserved SNARE-mediated exocytosis events. Thus, we provide here an up-to-date historical review of advancements in defining the roles and molecular mechanisms of Munc18-syntaxin complexes in the pathophysiology of Type 2 diabetes.

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“…Furthermore, Munc18c, which is attached to syntaxin 4 and, along with other proteins, inhibits attachment of vesicle-associated membrane protein 2 and other soluble N-ethylmaleimide-sensitive fusion protein attachment proteins required for vesicle docking and subsequent fusion of GLUT4 vesicles to the plasma membrane, is phosphorylated by PKCs and thereby released from syntaxin 4. In this regard, an 80-kDa protein appears to serve as a link between aPKC and Munc18c during insulin-induced translocation of GLUT4 vesicles to the plasma membrane (43). In addition to these docking mechanisms, aPKC appears to be required for alterations in cytoskeletal actin required during GLUT4 vesicle translocation (27); however, the aPKC-regulated molecular factors required in actin remodeling are unknown.…”

Section: Apkc Requirement In Insulin-stimulated Glucose Transportmentioning

confidence: 99%

Metabolic functions of atypical protein kinase C: “good” and “bad” as defined by nutritional status

Farese

Sajan

2010

American Journal of Physiology-Endocrinology and Metabolism

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tein kinase C (aPKC) isoforms mediate insulin effects on glucose transport in muscle and adipose tissues and lipid synthesis in liver and support other metabolic processes, expression of enzymes needed for islet insulin secretion and hepatic glucose production/release, CNS appetite suppression, and inflammatory responses. In muscle, selective aPKC deficiency impairs glucose uptake and produces insulin resistance and hyperinsulinemia, which, by activating hepatic aPKC, provokes inordinate increases in lipid synthesis and produces typical "metabolic syndrome" features. In contrast, hepatic aPKC deficiency diminishes lipid synthesis and protects against metabolic syndrome features. Unfortunately, aPKC is deficient in muscle but paradoxically conserved in liver in obesity and type 2 diabetes mellitus; this combination is particularly problematic because it promotes lipid and carbohydrate abnormalities. Accordingly, metabolic effects of aPKCs can be "good" or "bad," depending upon nutritional status; thus, muscle glucose uptake, islet insulin secretion, hepatic glucose and lipid production/release, and adipose fat synthesis/ storage would be important for survival during periods of limited food availability and therefore be "good." However, during times of food surfeit, excessive activation of hepatic aPKC, whether caused by overnutrition or impairments in extrahepatic effects of insulin, would lead to inordinate increases in hepatic lipid synthesis and metabolic syndrome features and therefore be "bad." In keeping with these ideas, the inhibition of hepatic aPKC markedly ameliorates lipid and carbohydrate abnormalities in experimental models of obesity and type 2 diabetes. We postulate that a similar approach may be useful for treating humans.ATYPICAL PROTEIN KINASE C (aPKC) isoforms, aPKC, -, and -, are members of the phospholipid/lipid-regulated PKC family that are activated by acidic phospholipids, phosphatidylinositol-1,3,5-(PO 4 ) 3 (PIP 3 ), and phosphatidic acid (PA) rather than by the neutral lipid, diacylglycerol (DAG), and Ca ϩϩ , which activate "typical" PKCs. However, it is a misnomer to consider aPKCs as "atypical" relative to typical DAG-dependent/Ca ϩϩ -dependent classical/conventional PKCs (cPKCs␣, -␤, and -␥) and DAG-dependent/Ca ϩϩ -independent novel PKCs (nPKC␦, -ε, -, and -). This nomenclature reflects the historical order of discovery of cPKCs, nPKCs, and aPKCs rather than their biological importance. Indeed, aPKCs are archetypal protein kinases that have widespread occurrence throughout plant and animal kingdoms and are indispensable in a wide variety of essential cellular functions independent of typical PKCs.aPKCs participate importantly in regulating multiple cellular processes pertinent to this review, including 1) determination of cellular polarity and related functions, i.e., motility, adhesion, differentiation, and embryogenesis; 2) activation of the immune response transactivator NF-B via aPKC-dependent phosphorylation of both IKK␣/␤ (24), a kinase that phosphorylates the inhibitor of B...

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80K-H Acts as a Signaling Bridge in Intact Living Cells Between PKCζ and the GLUT4 Translocation Regulator Munc18c

Cited by 4 publications

References 1 publication

Identification of calcium-binding proteins associated with the human sperm plasma membrane

Identification of calcium-binding proteins associated with the human sperm plasma membrane

Exocytosis mechanisms underlying insulin release and glucose uptake: conserved roles for Munc18c and syntaxin 4

Metabolic functions of atypical protein kinase C: “good” and “bad” as defined by nutritional status

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