Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Saccharomyces cerevisiae homologs, Pkh1/2p, of the mammalian 3-phosphoinositide-dependent protein kinase 1 (PDK1) regulate the Pkc1-MAP kinase cascade and the partially parallel Ypk1/2p pathway(s) that control growth and cell integrity. Mammalian PDK1 is regulated by 3-phosphoinositides, whereas Pkh1/2p are regulated by sphingolipid long-chain bases (LCBs). Recently Pkh1/2p were found to complex with two related proteins, Pil1p (Ygr086) and Lsp1p (Ypl004). Because these two proteins are not related to any known protein we sought to characterize their functions. We show that Pkh1p phosphorylates both proteins in vitro in a reaction that is only weakly regulated by LCBs. In contrast, LCBs inhibit phosphorylation of Pil1p by Pkh2p, whereas LCBs stimulate phosphorylation of Lsp1p by Pkh2p. We find that Pil1p and Lsp1p down-regulate resistance to heat stress and, specifically, that they down-regulate the activity of the Pkc1p-MAP and Ypk1p pathways during heat stress. Pil1p and Lsp1p are thus the first proteins identified as regulators of Pkh1/2p. An unexpected finding was that the level of Ypk1p is greatly reduced in pkc1Delta cells, indicating that Pkc1p controls the level of Ypk1p. Homologs of Pil1p and Lsp1p are widespread in nature, and our results suggest that they may be negative regulators of PDK-like protein kinases and their downstream cellular pathways that control cell growth and survival.
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PMID:Pil1p and Lsp1p negatively regulate the 3-phosphoinositide-dependent protein kinase-like kinase Pkh1p and downstream signaling pathways Pkc1p and Ypk1p. 1501 21

All-trans retinoic acid and 9-cis-retinoic acid stimulate the activity of steroid sulfatase in HL60 acute myeloid leukemia cells in a concentration- and time-dependent manner. Neither of these 'natural retinoids' augmented steroid sulfatase activity in a HL60 sub-line that expresses a dominant-negative retinoic acid receptor alpha (RARalpha). Experiments with synthetic RAR and RXR agonists and antagonists suggest that RARalpha/RXR heterodimers play a role in the retinoid-stimulated increase in steroid sulfatase activity. The retinoid-driven increase in steroid sulfatase activity was attenuated by inhibition of phospholipase D (PLD), but not by inhibitors of phospholipase C. Experiments with inhibitors of protein kinase C (PKC) show that PKCalpha and PKCdelta play an important role in modulating the retinoid-stimulation of steroid sulfatase activity in HL60 cells. Furthermore, we show that pharmacological inhibition of the RAF-1 and ERK MAP kinases blocked the retinoid-stimulated increase in steroid sulfatase activity in HL60 cells and, by contrast, inhibition of the p38-MAP kinase or JNK-MAP kinase had no effect. Pharmacological inhibitors of the phosphatidylinositol 3-kinase, Akt, and PDK-1 also abrogated the retinoid-stimulated increase in steroid sulfatase activity in HL60 cells. These results show that crosstalk between the retinoid-stimulated genomic and non-genomic pathways is necessary to increase steroid sulfatase activity in HL60 cells.
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PMID:Retinoid-mediated stimulation of steroid sulfatase activity in myeloid leukemic cell lines requires RARalpha and RXR and involves the phosphoinositide 3-kinase and ERK-MAP kinase pathways. 1617 10

Src family tyrosine kinases (SFKs) are important regulators of epithelial cell growth and differentiation. Characterization of cellular mechanisms that regulate SFK activity will provide insights into the pathogenesis of diseases associated with increased SFK activity. Keratin 14-Fyn (K14) transgenic mice were derived to characterize the effect of Fyn on epidermal growth and differentiation in vivo. The epidermis of K14-Fyn mice is thickened, manifests prominent scale, and exhibits features consistent with hyperproliferation. Increased epidermal Fyn levels correlate with activation of p44/42 MAP kinases, STAT-3, and PDK-1, key signaling molecules that promote epithelial cell growth. The Src-activating and signaling molecule (Srcasm) is a substrate of SFKs that becomes tyrosine-phosphorylated downstream of the EGF receptor. In vitro, increased Srcasm levels promote activation of endogenous Fyn and keratinocyte differentiation. To study the in vivo effect of Srcasm upon Fyn, double transgenic lines were derived. K14-Fyn/Srcasm transgenic mice did not manifest the hyperproliferative phenotype. In contrast, K14-Fyn/Srcasm-P transgenic mice, which express a nonphosphorylatable Srcasm mutant, maintained the hyperproliferative phenotype. Resolution of the hyperproliferative phenotype correlated with reduced Fyn levels in vivo in three experimental systems: transgenic mice, primary keratinocytes, and cell lines. Biochemical studies revealed that Srcasm-dependent Fyn down-regulation requires Fyn kinase activity, phosphorylation of Srcasm, and the Srcasm GAT domain. Therefore, Srcasm is a novel regulator of Fyn promoting kinase down-regulation in a phosphorylation-dependent manner. Srcasm may act as a molecular "rheostat" for activated SFKs, and cellular levels of Srcasm may be important for regulating epithelial hyperproliferation associated with increased SFK activity.
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PMID:Srcasm corrects Fyn-induced epidermal hyperplasia by kinase down-regulation. 1704 29