While a plethora of extracellular molecules exist that modulate cellular functions via binding to membrane receptors inside the cell, their actions are mediated by relatively few signalling mechanisms. One of these is activation of phosphatidylinositol 3-kinase (PI-3K), which results in the generation of a membranerestricted second messenger, polyphosphatidylinositides containing a 3h-phosphate. How these molecules transduced the effects of agonists of PI-3K was unclear until the recent discovery that several protein kinases become activated upon exposure to 3h-phosphorylated inositol lipids. These enzymes include protein kinase B (PKB)\AKT and PtdIns(3,4,5)P $ -dependent kinases 1 and 2, the first two of which interact with 3h-phosphorylated ORIGINS OF AKTThe AKR strain of mice exhibit a high incidence of leukaemias and lymphomas from spontaneous thymoma [1]. A retrovirus termed AKT8 was isolated from one of these lines derived from a spontaneous thymoma. This virus was demonstrated to uniquely transform only mink lung cells (CCL64) in culture, while virus inoculated into newborn mice was shown to be tumorigenic [2]. The non-viral DNA component transduced from the mouse genome was subsequently identified, and two human homologues, AKT1 and AKT2, cloned [3]. The location of the human AKT locus was mapped to chromosome 14q32, proximal to the immunoglobulin-heavy-chain locus [4], a region frequently affected by translocations and inversions in human Tcell leukaemia\lymphoma, mixed-lineage childhood leukaemia and clonal T-cell proliferations in ataxia telangiectasia, supporting a role for this oncogene in formation of a variety of tumours [5]. Analysis of a panel of human tumours revealed a 20-fold amplification of AKT1 in a primary gastric adenocarcinoma. AKT2, on the other hand, was mapped to chromosome region 19q13.1-q13.2 and shown to be amplified and overexpressed in several ovarian carcinoma and pancreatic cancer cell lines [6,7]. A recent large-scale study of AKT2 alterations in ovarian and breast tumours revealed amplification in 12.1 % ovarian and 2.8 % breast carcinomas [8]. Furthermore, amplification of AKT2 was especially frequent in undifferentiated tumours, suggesting that AKT2 alterations may be associated with tumour aggressiveness.Abbreviations used : PI-3K, phosphatidylinositol 3-kinase ; PKB, protein kinase B ; PKA, protein kinase A ; PKC, protein kinase C ; RAC-PK, related to A-and C-kinase ; PH, pleckstrin homology ; PtdIns, phosphoinositide ; PDGF, platelet-derived growth factor ; EGF, epidermal growth factor ; bFGF, basic fibroblast growth factor ; IL, interleukin ; ERK, extracellular-signal-regulated kinase ; Btk, Bruton tyrosine kinase ; PDK, PtdIns(3,4,5)P 3 -dependent kinase ; MAPKAP, mitogen-activated protein kinase-activated protein ; SH2, Src homology 2 ; gag, group-specific antigen ; GLUT, glucose transporter ; GSK, glycogen synthase kinase ; PFK2, 6-phosphofructose-2-kinase ; IGF, insulin-like growth factor ; 4E-BP1, 4E-binding protein ; PHAS, pH-and acid-stable ; BCR-ABL, breakpoint...

Integrins are critical for the migration and function of leukocytes in inflammation. However, the interaction between integrin alpha(M) (CD11b), which has high expression in monocytes and macrophages, and Toll-like receptor (TLR)-triggered innate immunity remains unclear. Here we report that CD11b deficiency enhanced TLR-mediated responses in macrophages, rendering mice more susceptible to endotoxin shock and Escherichia coli-caused sepsis. CD11b was activated by TLR-triggered phosphatidylinositol 3-OH kinase (PI(3)K) and the effector RapL and fed back to inhibit TLR signaling by activating the tyrosine kinases Src and Syk. Syk interacted with and induced tyrosine phosphorylation of MyD88 and TRIF, which led to degradation of these adaptor molecules by the E3 ubiquitin ligase Cbl-b. Thus, TLR-triggered, active CD11b integrin engages in crosstalk with the MyD88 and TRIF pathways and subsequently inhibits TLR signaling in innate immune responses.

China is one of the countries with the highest incidence of gastric cancer. There are differences in epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selection between gastric cancer patients from the Eastern and Western countries. Non-Chinese guidelines cannot specifically reflect the diagnosis and treatment characteristics for the Chinese gastric cancer patients. The Chinese Society of Clinical Oncology (CSCO) arranged for a panel of senior experts specializing in all sub-specialties of gastric cancer to compile, discuss, and revise the guidelines on the diagnosis and treatment of gastric cancer based on the findings of evidence-based medicine in China and abroad. By referring to the opinions of industry experts, taking into account of regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted experts’ consensus judgement on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes. This guideline uses tables and is complemented by explanatory and descriptive notes covering the diagnosis, comprehensive treatment, and follow-up visits for gastric cancer.

AAA-PKB did not prevent actin bundling (membrane ruffling), though this response was PI 3-kinase dependent. Therefore, it is unlikely that AAA-PKB acted by inhibiting PI 3-kinase signaling. These results outline an important role for PKB␣/Akt1 in the stimulation of glucose transport by insulin in muscle cells in culture.Translocation of GLUT4 from an intracellular compartment to the plasma membrane largely accounts for the stimulation of glucose transport by insulin in skeletal muscle (16,31,38), cardiac muscle (48), and adipose cells (23,24). Two insulinresponsive cell lines also express this transporter: L6 rat skeletal myotubes (34, 40) and 3T3-L1 mouse adipocytes (24). Transfection of a molecularly engineered form of this transporter containing an exofacial epitope tag between the first and second transmembrane domains allows for the detection of surface transporters in intact cells. GLUT4 molecules with an exofacial epitope tag have been heterologously expressed in rat adipose cells (44, 51), 3T3-L1 adipocytes (26), CHO cells (12, 26), H9c2 cardiomyocytes (55), and rat 3Y1 cells (22). We have recently shown that stable expression of GLUT4myc in L6 myoblasts (L6-GLUT4myc myoblasts) mimics the response to insulin seen with endogenous GLUT4 in differentiated myotubes (29, 60).Insulin-induced translocation of GLUT4 to the plasma membrane requires the activity of phosphatidylinositol (PI) 3-kinase (47) in rat adipocytes (43, 45), 3T3-L1 adipocytes (8,9,21,27,39,51), L6 muscle cells (53), and rat skeletal muscle (62). Moreover, treatment of intact 3T3-L1 adipocytes with a cell-permeant PI 3,4,5-triphosphate [PI (3,4,5)-P 3 ] compound, which is converted into a product of PI 3-kinase once inside the cell, partly rescued the inhibition of insulin-stimulated glucose transport by wortmannin (25). It is unclear how the lipid products of PI 3-kinase relay the insulin signal to the glucose transporters, but the serine/threonine kinase protein kinase B (PKB)/Akt interacts with the lipid products of PI 3-kinase (19), and activation of PKB/Akt by insulin is prevented by inhibitors of PI 3-kinase (1). To date, three isoforms of PKB/Akt have been identified: PKB␣, -␤, and -␥ (Akt1, -2, and -3) (17). In skeletal muscle and L6 muscle cells, PKB␣ and PKB␥, but not PKB␤, are stimulated by insulin (59). Full activation of PKB/ Akt by insulin requires hierarchical phosphorylation on two residues, Thr308 (Thr309 and Thr305 in the case of PKB␤ and -␥, respectively) and Ser473 (Ser474 in the case of PKB␤; PKB␥ lacks an equivalent site) by 3-phosphoinositide-dependent protein kinase 1 (PDK-1) and PDK-2, respectively (1-3, 14, 50).Recent reports have suggested that activation of PKB/Akt may mediate the stimulation of glucose transport by insulin, since stable overexpression of wild-type PKB␣/Akt1 or constitutively active mutants of PKB␣/Akt1 increased glucose transport and translocation of GLUT4 to levels similar to or greater than those achieved with insulin in rat adipocytes (52), 3T3-L1 adipocytes (33,56), and L6 muscle cells (20,56...

N 6-Methyladenosine (m6A) is the most abundant RNA modification in mammal mRNAs and increasing evidence suggests the key roles of m6A in human tumorigenesis. However, whether m6A, especially its ‘reader’ YTHDF1, targets a gene involving in protein translation and thus affects overall protein production in cancer cells is largely unexplored. Here, using multi-omics analysis for ovarian cancer, we identified a novel mechanism involving EIF3C, a subunit of the protein translation initiation factor EIF3, as the direct target of the YTHDF1. YTHDF1 augments the translation of EIF3C in an m6A-dependent manner by binding to m6A-modified EIF3C mRNA and concomitantly promotes the overall translational output, thereby facilitating tumorigenesis and metastasis of ovarian cancer. YTHDF1 is frequently amplified in ovarian cancer and up-regulation of YTHDF1 is associated with the adverse prognosis of ovarian cancer patients. Furthermore, the protein but not the RNA abundance of EIF3C is increased in ovarian cancer and positively correlates with the protein expression of YTHDF1 in ovarian cancer patients, suggesting modification of EIF3C mRNA is more relevant to its role in cancer. Collectively, we identify the novel YTHDF1-EIF3C axis critical for ovarian cancer progression which can serve as a target to develop therapeutics for cancer treatment.