The extracellular signal-regulated kinase (ERK) cascade is a central pathway that transmits signals from many extracellular agents to regulate cellular processes such as proliferation, differentiation and cell cycle progression. The signaling via the ERK cascade is mediated by sequential phosphorylation and activation of protein kinases in the different tiers of the cascade. Although the main core phosphorylation chain of the cascade includes Raf kinases, MEK1/2, ERK1/2 (ERKs) and RSKs, other alternatively spliced forms and distinct components exist in the different tiers, and participate in ERK signaling under specific conditions. These components enhance the complexity of the ERK cascade and thereby, enable the wide variety of functions that are regulated by it. Another factor that is important for the dissemination of ERKs' signals is the multiplicity of the cascade's substrates, which include transcription factors, protein kinases and phosphatases, cytoskeletal elements, regulators of apoptosis, and a variety of other signaling-related molecules. About 160 substrates have already been discovered for ERKs, and the list of these substrates, as well as the function and mechanism of activation of representative substrates, are described in the current review. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Understanding of these processes may provide a full picture of the distinct, and even opposing cellular processes that are regulated by the ERK cascade.

The extracellular signal-regulated kinase: Multiple substrates regulate diverse cellular functions

Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer

https://pure.hw.ac.uk/ws/files/24014028/1_s2.0_S1044579X18300592_main.pdf

Mechanisms of PTEN loss in cancer: it’s all about diversity

The FRS2 family of adaptor/scaffold proteins has two members, FRS2alpha and FRS2beta. Both proteins contain N-terminal myristylation sites for localization on the plasma membrane and a PTB domain for binding to limited species of receptor tyrosine kinases (RTKs), including the FGF receptor, the neurotophin receptor, RET, and ALK. Activation of these RTKs allows FRS2 proteins to become phosphorylated of tyrosine residues and then bind to Grb2 and Shp2, a SH2 domain-containing adaptor and a tyrosine phosphatase, respectively. Subsequently, Shp2 activates a Ras/ERK pathway and Grb2 activates a Ras/ERK, phosphatidyl inositol (PI)-3 kinase and ubiquitination/degradation pathways by binding to SOS, Gab1, and Cbl via the SH3 domains of Grb2. FRS2alpha acts as 'a conning center' in FGF signaling mainly because it induces sustained levels of activation of ERK via Shp2-binding sites and Grb2-binding sites, though the contribution of the former is greater. Indeed, FRS2alpha knockout mice and mice with mutated Shp2-binding sites exhibit a variety of phenotypes due to defects in FGF signaling in vivo. Although FRS2beta binds to the EGF receptor, it does not induce tyrosine phosphorylation on the receptor. Instead, it inhibits EGF signaling, resulting in inhibition of EGF-induced cell proliferation and cell transformation. Based on these findings, the involvement of FRS2 proteins in tumorigenesis should be studied extensively to be validated as candidate biomarkers for the effectiveness of treatments targeting RTKs such as the FGF receptor and EGF receptor.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1349-7006.2008.00840.x

Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins

RAF-MEK-ERK pathway in cancer evolution and treatment.

Phosphatase and tensin homologue (PTEN) triggers a battery of intracellular signaling pathways, especially PI3K/Akt, playing important roles in the pathogenesis of multiple diseases, such as cancer, neurodevelopmental disorders, cardiovascular dysfunction and so on. Therefore PTEN might be a biomarker for various diseases, and targeting the abnormal expression level of PTEN is anticipated to offer novel therapeutic avenues. Recently, noncoding RNAs (ncRNAs) have been reported to regulate protein expression, and it is definite that PTEN expression is controlled by ncRNAs epigenetically or posttranscriptionally as well. Herein, we provide a review on current understandings of the regulation of PTEN by ncRNAs, which could contribute to the development of novel approaches to the diseases with abnormal expression of PTEN.

/pdf/regulation-of-pten-expression-by-noncoding-rnas-34qcbw0ftj.pdf

Regulation of PTEN expression by noncoding RNAs

// Dan Lv 1, * , Lianying Guo 1, * , Ting Zhang 1 and Lin Huang 1 1 Department of Pathophysiology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China * These authors contributed equally to this work Correspondence to: Lin Huang, email: lhuang@dmu.edu.cn Keywords: PRAS40, Akt, mTOR, signaling, tumorigenesis Received: December 14, 2016      Accepted: April 11, 2017      Published: April 20, 2017 ABSTRACT The proline-rich Akt substrate of 40 kDa (PRAS40) is a substrate of Akt and a component of the mammalian target of rapamycin complex 1 (mTORC1). Locating at the crossroad of the PI3K/Akt pathway and the mTOR pathway, PRAS40 is phosphorylated by growth factors or other stimuli, and regulates the activation of these signaling pathways in turn. PRAS40 plays an important role in metabolic disorders and multiple cancers, and the phosphorylation of PRAS40 is often associated with the tumor progression of melanoma, prostate cancer, etc. PRAS40 promotes tumorigenesis by deregulating cellular proliferation, apoptosis, senescence, metastasis, etc. Herein, we provide an overview on current understandings of PRAS40 signaling in the tumor formation and progression, which suggests that PRAS40 or phospho-PRAS40 could become a novel biomarker and therapeutic target in tumor.

/pdf/pras40-signaling-in-tumor-beiledbgi8.pdf

PRAS40 signaling in tumor.

Translational repression by the oocyte-specific protein P100 in Xenopus

// Hongjiu Yu 1,2,* , Yonggui Ge 1,* , Lianying Guo 1,* and Lin Huang 1 1 Department of Pathophysiology, Dalian Medical University, Dalian, Liaoning, P.R. China 2 Department of VIP, The First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, P.R. China * These authors have contributed equally to this work Correspondence to: Lin Huang, email: // Keywords : Ewing’s sarcoma, targeted therapy, immunotherapy Received : June 21, 2016 Accepted : October 03, 2016 Published : October 11, 2016 Abstract Ewing’s sarcoma (ES) is a highly aggressive and metastatic tumor in children and young adults caused by a chromosomal fusion between the Ewing sarcoma breakpoint region 1 ( EWSR1 ) gene and the transcription factor FLI1 gene. ES is managed with standard treatments, including chemotherapy, surgery and radiation. Although the 5-year survival rate for primary ES has improved, the survival rate for ES patients with metastases or recurrence remains low. Several novel molecular targets in ES have recently been identified and investigated in preclinical and clinical settings, and targeting the function of receptor tyrosine kinases (RTKs), the fusion protein EWS-FLI1 and mTOR has shown promise. There has also been increasing interest in the immune responses of ES patients. Immunotherapies using T cells, NK cells, cancer vaccines and monoclonal antibodies have been considered for ES, especially for recurrent patients. Because understanding the pathogenesis of ES is extremely important for the development of novel treatments, this review focuses on the mechanisms and functions of targeted therapies and immunotherapies in ES. It is anticipated that integrating the knowledge obtained from basic research and translational and clinical studies will lead to the development of novel therapeutic strategies for the treatment of ES.

/pdf/potential-approaches-to-the-treatment-of-ewing-s-sarcoma-3ey4mvvzrf.pdf

Potential approaches to the treatment of Ewing's sarcoma.

A new ERK2 binding protein, Naf1, attenuates the EGF/ERK2 nuclear signaling.

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