Mitogen-activated protein kinase (MAPK) cascades are key signalling pathways that regulate a wide variety of cellular processes, including proliferation, differentiation, apoptosis and stress responses. The MAPK pathway includes three main kinases, MAPK kinase kinase, MAPK kinase and MAPK, which activate and phosphorylate downstream proteins. The extracellular signal-regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that regulate cellular signalling under both normal and pathological conditions. ERK expression is critical for development and their hyperactivation plays a major role in cancer development and progression. The Ras/Raf/MAPK (MEK)/ERK pathway is the most important signalling cascade among all MAPK signal transduction pathways, and plays a crucial role in the survival and development of tumour cells. The present review discusses recent studies on Ras and ERK pathway members. With respect to processes downstream of ERK activation, the role of ERK in tumour proliferation, invasion and metastasis is highlighted, and the role of the ERK/MAPK signalling pathway in tumour extracellular matrix degradation and tumour angiogenesis is emphasised. signalling elements that regulate basic processes including cell proliferation, differentiation and stress responses (1-3). These cascades transmit signals through sequential activation of three to five layers of protein kinases known as MAPK kinase kinase kinase (MAP4K), MAPK kinase kinase (MAP3K), MAPK kinase (MAPKK), MAPK and MAPK-activated protein kinases (MAPKAPK). The first three central layers are considered as a basic core unit, while the last two layers appear in some cascades and can vary among cells and stimuli. Four MAPK cascades have been defined based on the components in the MAPK layer: ERK1/2, c-Jun N-terminal kinase (JNK), p38 MAPK and ERK5. This review focuses on the ERK cascade (4-6) which involves several kinases in the MAP3K layer (mainly Rafs), including Ras/Raf/MAPK (MEK) 1/2 at the MAPKK layer, ERK1/2 at the MAPK layer and several MAPKAPKs in the next layer (ribosomal s6 kinases, MAP kinase-interacting serine/threonine-protein kinases, mitogen-and stress-activated protein kinases and cytosolic phospholipase A2). ERK cascades are highly regulated cascades that are responsible for basic cellular processes, including cell proliferation and differentiation. These regulatory factors affect bispecific phosphatases (7-10), scaffold proteins (11-14), signal duration and intensity (15), and the dynamic subcellular localization of cascade components (16,17). Due to the importance of the ERK cascade, ERK disorders are harmful to cells and ultimately to the body. Excessive activation of upstream proteins and kinases in the ERK pathway has been shown to induce various diseases, including cancer, inflammation, developmental disorders and neurological disorders (18-22). Since ERK1 and ERK2 are very similar, the singular form of ERK is used in this review, although two subtypes exist. Dysfunction in the Ras-ERK pat...

OBJECTIVEIt remains unclear how many hours of sleep are associated with the lowest risk of type 2 diabetes. This meta-analysis was performed to assess the dose-response relationship between sleep duration and risk of type 2 diabetes. RESEARCH DESIGN AND METHODSPubMed and Embase were searched up to 20 March 2014 for prospective observational studies that assessed the relationship of sleep duration and risk of type 2 diabetes. Both semiparametric and parametric methods were used. RESULTSTen articles with 11 reports were eligible for inclusion in the meta-analysis. A total of 18,443 incident cases of type 2 diabetes were ascertained among 482,502 participants with follow-up periods ranging from 2.5 to 16 years. A U-shaped dose-response relationship was observed between sleep duration and risk of type 2 diabetes, with the lowest risk observed at a sleep duration category of 7-8 h per day. Compared with 7-h sleep duration per day, the pooled relative risks for type 2 diabetes were 1.09 (95% CI 1.04-1.15) for each 1-h shorter sleep duration among individuals who slept <7 h per day and 1.14 (1.03-1.26) for each 1-h increment of sleep duration among individuals with longer sleep duration. CONCLUSIONS

Key messagesd This large-scale cross-trait GWAS provides strong evidence for shared genetic components between obesityrelated metabolic traits and asthma subtypes.d The strongest positive genetic correlation was observed between obesity and later-onset asthma.d Mendelian randomization analysis provided strong evidence in support of BMI causally increasing the risk of asthma.

ObjectivesTo prospectively evaluate the joint association of duration of rotating night shift work and lifestyle factors with risk of type 2 diabetes risk, and to quantitatively decompose this joint association to rotating night shift work only, to lifestyle only, and to their interaction.DesignProspective cohort study.SettingNurses’ Health Study (1988-2012) and Nurses’ Health Study II (1991-2013).Participants143 410 women without type 2 diabetes, cardiovascular disease, or cancer at baseline.ExposuresRotating night shift work was defined as at least three night shifts per month in addition to day and evening shifts in that month. Unhealthy lifestyles included current smoking, physical activity levels below 30 minutes per day at moderate to vigorous intensity, diet in the bottom three fifths of the Alternate Healthy Eating Index score, and body mass index of 25 or above.Main outcome measuresIncident cases of type 2 diabetes were identified through self report and validated by a supplementary questionnaire.ResultsDuring 22-24 years of follow-up, 10 915 cases of incident type 2 diabetes occurred. The multivariable adjusted hazard ratios for type 2 diabetes were 1.31 (95% confidence interval 1.19 to 1.44) per five year increment of duration of rotating night shift work and 2.30 (1.88 to 2.83) per unhealthy lifestyle factor (ever smoking, low diet quality, low physical activity, and overweight or obesity). For the joint association of per five year increment rotating night shift work and per unhealthy lifestyle factor with type 2 diabetes, the hazard ratio was 2.83 (2.15 to 3.73) with a significant additive interaction (P for interaction <0.001). The proportions of the joint association were 17.1% (14.0% to 20.8%) for rotating night shift work alone, 71.2% (66.9% to 75.8%) for unhealthy lifestyle alone, and 11.3% (7.3% to 17.3%) for their additive interaction.ConclusionsAmong female nurses, both rotating night shift work and unhealthy lifestyle were associated with a higher risk of type 2 diabetes. The excess risk of rotating night shift work combined with unhealthy lifestyle was higher than the addition of risk associated with each individual factor. These findings suggest that most cases of type 2 diabetes could be prevented by adhering to a healthy lifestyle, and the benefits could be greater in rotating night shift workers.