Generation of intracellular domain of insulin receptor tyrosine kinase by γ-secretase

Kasuga, Kensaku; Kaneko, Hiroyuki; Nishizawa, Masatoyo; Onodera, Osamu; Ikeuchi, Takeshi

doi:10.1016/j.bbrc.2007.06.022

Cited by 49 publications

(43 citation statements)

References 29 publications

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“…In preliminary reports, it has been shown that the insulin and IGF-1 receptors can be cleavaged by secretase action to produce ICD fragments (Kasuga et al 2007;McElroy et al 2007). However, although TPA stimulated formation of the ICD fragments neither cognate ligand was shown to do so.…”

Section: Insulin-like Growth Factor-1 and Insulin Receptorsmentioning

confidence: 99%

Receptor Tyrosine Kinases in the Nucleus

Carpenter

Liao

2013

Cold Spring Harbor Perspectives in Biology

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To date, 18 distinct receptor tyrosine kinases (RTKs) are reported to be trafficked from the cell surface to the nucleus in response to ligand binding or heterologous agonist exposure. In most cases, an intracellular domain (ICD) fragment of the receptor is generated at the cell surface and translocated to the nucleus, whereas for a few others the intact receptor is translocated to the nucleus. ICD fragments are generated by several mechanisms, including proteolysis, internal translation initiation, and messenger RNA (mRNA) splicing. The most prevalent mechanism is intramembrane cleavage by g-secretase. In some cases, more than one mechanism has been reported for the nuclear localization of a specific RTK. The generation and use of RTK ICD fragments to directly communicate with the nucleus and influence gene expression parallels the production of ICD fragments by a number of non-RTK cell-surface molecules that also influence cell proliferation. This review will be focused on the individual RTKs and to a lesser extent on other growth-related cell-surface transmembrane proteins.

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Section: Insulin-like Growth Factor-1 and Insulin Receptorsmentioning

confidence: 99%

Receptor Tyrosine Kinases in the Nucleus

Carpenter

Liao

2013

Cold Spring Harbor Perspectives in Biology

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“…HEK293 cell lines stably expressing either human wild-type presenilin 1 (PS1 WT) or a dominant-negative PS1 variant (substitution of Asp at 385 for Ala, PS1 D385A) (16) were kindly provided by Takeshi Ikeuchi (Niigata University, Niigata, Japan). These cells were transfected with Ptprz expression plasmids by calcium-phosphate precipitation as described (17).…”

Section: Methodsmentioning

confidence: 99%

Metalloproteinase- and γ-Secretase-mediated Cleavage of Protein-tyrosine Phosphatase Receptor Type Z

Chow

Fujikawa

Shimizu

et al. 2008

Journal of Biological Chemistry

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Protein-tyrosine phosphatase receptor type Z (Ptprz) is preferentially expressed in the brain as a major chondroitin sulfate proteoglycan. Three splicing variants, two receptor isoforms and one secretory isoform, are known. Here, we show that the extracellular region of the receptor isoforms of Ptprz are cleaved by metalloproteinases, and subsequently the membrane-tethered fragment is cleaved by presenilin/␥-secretase, releasing its intracellular region into the cytoplasm; of note, the intracellular fragment of Ptprz shows nuclear localization. Administration of GM6001, an inhibitor of metalloproteinases, to mice demonstrated the metalloproteinase-mediated cleavage of Ptprz under physiological conditions. Furthermore, we identified the cleavage sites in the extracellular juxtamembrane region of Ptprz by tumor necrosis factor-␣ converting enzyme and matrix metalloproteinase 9. This is the first evidence of the metalloproteinase-mediated processing of a receptor-like protein-tyrosine phosphatase in the central nervous system.Receptor-like protein-tyrosine phosphatases (RPTPs) 2 are a structurally and functionally diverse family of enzymes comprised of eight subfamilies (1). Protein-tyrosine phosphatase receptor type Z (Ptprz, also called PTP or RPTP␤) is a RPTP classified in the R5 subfamily and expressed in neuronal and glial cells in the central nervous system (2-4). The physiological importance of this molecule has been demonstrated through studies of Ptprz-deficient mice (4, 5), which display impairments in hippocampal function in a maturation-dependent manner (6, 7). An independently generated knock-out mouse line suggests a fragility of myelin in the central nervous system (8).It is known that three isoforms of Ptprz are generated by alternative splicing from a single Ptprz gene (on mouse chromosome 6; human chromosome 7), the two transmembrane isoforms Ptprz-A and Ptprz-B and the secretory isoform Ptprz-S (also known as 6B4 proteoglycan or phosphacan) (2, 9 -12), all of which are expressed as chondroitin sulfate proteoglycans in the brain (3). However, some inexplicable issues about the molecular profiles of Ptprz have remained in previous studies. For instance, although there exists substantial expression of the respective transcripts for all isoforms (11, 13), fulllength Ptprz-A has been scarcely observed at the protein level in the adult brain (3, 4). In addition, several lower molecular species have been detected with a specific antibody against Ptprz in wild-type mice (4). The technical difficulty in removal of the chondroitin sulfate chains to separate their core proteins by SDS-PAGE may induce variability in the signal patterns of this molecule in Western blotting among researchers.In this study we examined the molecular profile of Ptprz in the adult mouse brain at both protein and mRNA levels in detail and revealed that the proteolytic fragments are abundantly accumulated. The two receptor isoforms were found to undergo ectodomain cleavage by metalloproteinases, releasing their extracellular fragm...

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“…1). However, the IR level was slightly enhanced in WT MEF cells treated with DAPT, indicating that this enhancement could be caused by the inhibition of IR cleavage by ␥-secretase (15).…”

Section: Insulin-mediated Phosphorylation Of Akt Is Enhanced In ϫ/ϫmentioning

confidence: 92%

“…This activation subsequently phosphorylates intracellular substrates, which have roles in cell growth, energy metabolism, cholinergic gene expression, inhibition of oxidative stress, and apoptosis (14). Notably, it has been reported that ␥-secretase processes IR along with other substrates (15,16). Therefore, in this study, we directed our attention to IR, which belongs to the tyrosine kinase family, and hypothesized that IR/insulin signaling may also be regulated by PS.…”

mentioning

confidence: 99%

Presenilin Regulates Insulin Signaling via a γ-Secretase-independent Mechanism

Maesako

Uemura

Kuzuya

et al. 2011

Journal of Biological Chemistry

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Presenilin (PS), a causative molecule of familial Alzheimer disease, acts as a crucial component of the ␥-secretase complex, which is required to cleave type I transmembrane proteins such as amyloid precursor protein and Notch. However, it also functions through ␥-secretase-independent pathways. Recent reports suggested that PS could regulate the expression level of cell surface receptors, including the PDGF and EGF receptors, followed by modulating their downstream pathways via ␥-secretase-independent mechanisms. The main purpose of this study was to clarify the effect of PS on expression of the insulin receptor (IR) as well as on insulin signaling. Here, we demonstrate that PS inhibited IR transcription and reduced IR expression, and this was followed by down-regulation of insulin signaling. Moreover, we suggest that neither ␥-secretase activity nor Wnt/ ␤-catenin signaling can reduce the expression of IR, but a PSmediated increase in the intracellular Ca 2؉ level can be associated with it. These results clearly indicate that PS can functionally regulate insulin signaling by controlling IR expression.

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Generation of intracellular domain of insulin receptor tyrosine kinase by γ-secretase

Cited by 49 publications

References 29 publications

Receptor Tyrosine Kinases in the Nucleus

Receptor Tyrosine Kinases in the Nucleus

Metalloproteinase- and γ-Secretase-mediated Cleavage of Protein-tyrosine Phosphatase Receptor Type Z

Presenilin Regulates Insulin Signaling via a γ-Secretase-independent Mechanism

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