Calmodulin-mediated Activation of Akt Regulates Survival of c-Myc-overexpressing Mouse Mammary Carcinoma Cells

Deb, Tushar B.; Coticchia, Christine M.; Dickson, Robert B.

doi:10.1074/jbc.m405314200

Cited by 89 publications

(92 citation statements)

References 87 publications

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“…These results suggest that Trpv5 Intracellular Ca 2 þ /CaM-dependent signaling has been implicated in Akt activation in cultured mammalian cells. 23 We tested the possible role of intracellular Ca 2 þ and/or CaM signaling in mediating the Trpv5/6 effect using the intracellular , and raised to 120 hpf. NaR cell density was determined as described in (e).…”

Section: Resultsmentioning

confidence: 99%

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

et al. 2013

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Calcium deficiency causes abnormal colonic growth and increases colon cancer risk with poorly understood mechanisms. Here we elucidate a novel signaling mechanism underlying the Ca 2 þ deficiency-induced epithelial proliferation using a unique animal model. The zebrafish larval yolk sac skin contains a group of Ca 2 þ -transporting epithelial cells known as ionocytes. Their number and density increases dramatically when acclimated to low [Ca 2 þ ] environments. BrdU pulse-labeling experiments suggest that low [Ca 2 þ ] stimulates pre-existing ionocytes to re-enter the cell cycle. Low [Ca 2 þ ] treatment results in a robust and sustained activation of IGF1R-PI3K-Akt signaling in these cells exclusively. These ionocytes specifically express Igfbp5a, a high-affinity and specific binding protein for insulin-like growth factors (IGFs) and the Ca 2 þ -selective channel Trpv5/6. Inhibition or knockdown of Igfbp5a, IGF1 receptor, PI3K, and Akt attenuates low [Ca 2 þ ]-induced ionocyte proliferation. The role of Trpv5/6 was investigated using a genetic mutant, targeted knockdown, and pharmacological inhibition. Loss-of-Trpv5/6 function or expression results in elevated pAkt levels and increased ionocyte proliferation under normal [Ca 2 þ ]. These increases are eliminated in the presence of an IGF1R inhibitor, suggesting that Trpv5/6 represses IGF1R-PI3K-Akt signaling under normal [Ca 2 þ ]. Intriguingly, blockade of Trpv5/6 activity inhibits the low [Ca 2 þ ]-induced activation of Akt. Mechanistic analyses reveal that the low [Ca 2 þ ]-induced IGF signaling is mediated through Trpv5/6-associated membrane depolarization. Low extracellular [Ca 2 þ ] results in a similar amplification of IGF-induced PI3K-PDK1-Akt signaling in human colon cancer cells in a TRPV6-dependent manner. These results uncover a novel and evolutionarily conserved signaling mechanism that contributes to the abnormal epithelial proliferation associated with Ca 2 þ deficiency.

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Section: Resultsmentioning

confidence: 99%

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

et al. 2013

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“…Inositol 1,4,5-triphosphate stimulates the release of intracellular Ca 21 from the endoplasmic reticulum, which further serves as a signaling molecule, activating a number of intracellular enzymes, including PKC, PI3K, Akt, and cPLA 2 (44)(45)(46). All of these enzymes are involved in the ASP pathway (as discussed below), explaining the effective inhibition by Ca 21 chelation of the ASP signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Targeting the signaling pathway of acylation stimulating protein

Maslowska

Legakis

Assadi

et al. 2006

Journal of Lipid Research

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Acylation stimulating protein (ASP; C3adesArg) stimulates triglyceride synthesis (TGS) and glucose transport in preadipocytes/adipocytes through C5L2, a G-proteincoupled receptor. Here, ASP signaling is compared with insulin in 3T3-L1 cells. ASP stimulation is not Ga s or Ga i mediated (pertussis and cholera toxin insensitive), suggesting G aq as a candidate. Phospholipase C (PLC) is required, because the Ca 21 chelator 1,2-bis(o-aminophenoxy) ethane-N,N,N9,N9-tetraacetic acid tetra(acetoxymethyl) ester and the PLC inhibitor U73122 decreased ASP stimulation of TGS by 93.1% (P , 0.0.001) and 86.1% (P , 0.004), respectively. Wortmannin and LY294002 blocked ASP effect by 69% (P , 0.001) and 116.1% (P , 0.003), respectively, supporting phosphatidylinositol 3-kinase (PI3K) involvement. ASP induced rapid, transient Akt phosphorylation (maximal, 5 min; basal, 45 min), which was blocked by Akt inhibition, resembling treatment by insulin. Downstream of PI3K, mamalian target of rapaycin (mTOR) is required for insulin but not ASP action. By contrast, both ASP and insulin activate the mitogen-activated protein kinase/extracellular signalregulated kinase (MAPK/ERK 1/2 ) pathway, with rapid, pronounced increases in ERK 1/2 phosphorylation, effects partially blocked by PD98059 (64.7% and 65.9% inhibition, respectively; P , 0.001). Time-dependent (maximal, 30 min) transient calcium-dependent phospholipase A 2 (cPLA 2 ) -Ser505

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“…It was reported that PLC-␥2, a homologue of PLC-␥1, is required for B cell receptor-mediated cell survival (Bell et al, 2004). Akt activation is abolished by the PLC-␥1 inhibitor U73122, which suggests a possible role of PLC-␥1 in EGF-induced cell survival through the interaction with Akt (Deb et al, 2004). Therefore, whether the interaction between PLC-␥1 and Akt regulates cell survival warrants future research.…”

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confidence: 98%

Akt Binds to and Phosphorylates Phospholipase C-γ1 in Response to Epidermal Growth Factor

Wang

2006

MBoC

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Both phospholipase (PL) C-␥1 and Akt (protein kinase B; PKB) are signaling proteins that play significant roles in the intracellular signaling mechanism used by receptor tyrosine kinases, including epidermal growth factor (EGF) receptor (EGFR). EGFR activates PLC-␥1 directly and activates Akt indirectly through phosphatidylinositol 3-kinase (PI3K). Many studies have shown that the PLC-␥1 pathway and PI3K-Akt pathway interact with each other. However, it is not known whether PLC-␥1 binds to Akt directly. In this communication, we identified a novel interaction between PLC-␥1 and Akt. We demonstrated that the interaction is mediated by the binding of PLC-␥1 Src homology (SH) 3 domain to Akt proline-rich motifs. We also provide a novel model to depict how the interaction between PLC-␥1 SH3 domain and Akt proline-rich motifs is dependent on EGF stimulation. In this model, phosphorylation of PLC-␥1 Y783 by EGF causes the conformational change of PLC-␥1 to allow the interaction of its SH3 domain with Akt proline-rich motifs. Furthermore, we showed that the interaction between PLC-␥1 and Akt resulted in the phosphorylation of PLC-␥1 S1248 by Akt. Finally, we showed that the interaction between PLC-␥1 and Akt enhanced EGF-stimulated cell motility. INTRODUCTIONThe stimulatory effects of receptor tyrosine kinases (RTKs) on cell growth are mediated by downstream signaling proteins. Phospholipase (PL) C-␥1 is one of these signaling proteins and plays a significant role in the intracellular signaling mechanism used by RTKs (Wahl and Carpenter, 1991). PLC-␥1 has been implicated in many growth factor (GF)-induced cell signaling processes, including cell proliferation, differentiation, receptor endocytosis, cell motility, membrane ruffle formation, and branching tubulogenesis (Wahl and Carpenter, 1991;Kamat and Carpenter, 1997;Wells et al., 1998;Gual et al., 2000;Bivona et al., 2003;Chou et al., 2003;Meyer et al., 2003;Choi et al., 2004). Overexpression and hyperactivation of PLC-␥1 have been implicated in breast and prostate cancers. Especially, PLC-␥1 activity has been linked to cancer cell invasion (Thomas et al., 2003;Wells and Grandis, 2003).PLC-␥1, a 145-kDa protein, contains two Src homology (SH) 2 domains, one SH3 domain, and two pleckstrin homology (PH) domains and catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate, creating inositol 1,4,5-triphosphate (IP 3 ) and diacylglycerol. These second messengers are known to stimulate the release of Ca 2ϩ from internal stores and to activate protein kinase C (PKC), respectively (Wahl and Carpenter, 1991). PLC-␥1 forms a complex in vivo with epidermal growth factor (EGF) receptor (EGFR) through its SH2 domain interaction (Wahl et al., 1988;Margolis et al., 1989Margolis et al., , 1990Meisenhelder et al., 1989;Anderson et al., 1990). Complex formation leads to phosphorylation of PLC-␥1 on tyrosine residues and an increase in its enzymatic activity (Kim et al., 1991;Ronnstrand et al., 1992;Rotin et al., 1992).All of the PLC-␥1 domains have been implicated in regulati...

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Calmodulin-mediated Activation of Akt Regulates Survival of c-Myc-overexpressing Mouse Mammary Carcinoma Cells

Cited by 89 publications

References 87 publications

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

Targeting the signaling pathway of acylation stimulating protein

Akt Binds to and Phosphorylates Phospholipase C-γ1 in Response to Epidermal Growth Factor

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