整合素连接激酶(ILK)在肾脏疾病中的研究进展

整合素连接激酶（integrin-linked kinase,ILK）是一种丝氨酸/苏氨酸蛋白激酶,可与整合素β1、β3亚基胞浆域结合,参与整合素、生长因子、Wnt及TGF-β/Smad等多种信号转导,在调节细胞黏附、凋亡、转移、生长、细胞周期、肿瘤形成等过程中起重要作用。细胞中ILK表达异常,将引发病理变化。本文综述了ILK的生物学活性及其与肾脏疾病的关系,提示ILK的表达调控可能成为治疗肾脏疾病的新途径。     

Diabetic cardiovascular disease--AMP-activated protein kinase (AMPK) as a therapeutic target

Cardiovascular complications are the leading cause of death and morbidity in patients with diabetes; accounting for around 7 out of 10 of all causes of death in this population. Returning patients to normoglycaemia alone has been shown to have little effect on cardiovascular end points, therefore new therapies and strategies are required in order to reduce the incidence and improve outcomes of cardiovascular disease in diabetic individuals. The metabolic enzyme AMP-activated protein kinase (AMPK) has emerged in recent years as an attractive potential therapeutic target for diabetic vascular disease, and studies have shown improved endothelial and smooth muscle cell function following AMPK activation. Additionally, improved lipid profiles, reduced hypertrophic cardiomyocyte growth and protection from cardiac ischaemia-reperfusion injury have also been observed as beneficial outcomes of AMPK therapy. In this review we will discuss in detail the potential downstream targets of AMPK activation in the cardiovascular system. We will also provide an overview of long-known and newly discovered direct and indirect AMPK activators, as well as novel synthesised AMPK-activating compounds, which will highlight the potential for further exploiting AMPK in a therapeutic context for cardiovascular disease in diabetes.     

Anaplastic lymphoma kinase as a therapeutic target

Introduction: Anaplastic lymphoma kinase (ALK), a tyrosine kinase receptor, has been initially identified through its involvement in chromosomal translocations associated with anaplastic large cell lymphoma. However, recent evidence that aberrant ALK activity is also involved in an expanding number of tumor types, such as other lymphomas, inflammatory myofibroblastic tumor, neuroblastomas and some carcinomas, including non-small cell lung carcinomas, is boosting research progress in ALK-targeted therapies.

Areas covered: The first aim of this review is to describe current understandings about the ALK tyrosine kinase and its implication in the oncogenesis of human cancers as a fusion protein or through mutations. The second goal is to discuss its interest as a therapeutic target and to provide a review of the literature regarding ALK inhibitors. Mechanisms of acquired resistance are also reviewed.

Expert opinion: Several ALK inhibitors have recently been developed, offering new treatment options in tumors driven by abnormal ALK signaling. However, as observed with other tyrosine kinase inhibitors, resistance has emerged in patients treated with these agents. The complexity of mechanisms of acquired resistance recently described suggests that other therapeutic options, including combination of ALK and other kinases targeted drugs, will be required in the future.     

Bruton's tyrosine kinase as a new therapeutic target

Targeting Bruton's tyrosine kinase (BTK) with a small molecule inhibitor may be useful in treatment of BTK-expressing malignancies because of the anti-apoptotic function of BTK in cancer cells. Furthermore, BTK inhibitors also exhibit anti-thrombotic properties that may be desirable in the context of the increased risk of thromboembolic complications in cancer patients. This review will focus on the role of BTK in drug resistance in cancer, thromboembolism, and various pathologic immune responses, such as graft versus host disease. The therapeutic potential of targeting BTK is illustrated by discussion of the biologic activity profile of the rationally designed BTK inhibitor LFM-A13.     

Apoptosis signal-regulating kinase 1 as a therapeutic target

Introduction: All organisms are ordinarily exposed to various stresses. It is important for organisms to possess appropriate stress response mechanisms and to maintain homeostasis because the disruption of a stress response system can cause various diseases. Apoptosis signal-regulating kinase 1 (ASK1) is one of the stress-responsive MAP3Ks. ASK1 plays an important role in the response to reactive oxygen species (ROS), endoplasmic reticulum stress and pro-inflammatory cytokines, and it is involved in the pathogenesis of various diseases.

Areas covered: In this review, the authors describe recent literature concerning the intricate and elaborate regulation system of ASK1, the function of ASK1 during a cellular stress response and the involvement of ASK1 in many diseases, including cancer, neurodegenerative diseases, infections, diabetes and cardiovascular diseases.

Expert opinion: In certain disease conditions, ASK1 plays a protective role, whereas ASK1 can exacerbate the pathology of other diseases. Although ASK1 is involved in various diseases, there is no therapy or drug that targets ASK1 for use in a clinical setting. Recently, ASK1 inhibitors (K811 and MSC2032964A) have emerged, and their therapeutic potentials have been tested in vivo. ASK1 is currently receiving considerable attention as a new therapeutic target.     

Death-associated protein kinase as a potential therapeutic target

Death associated protein kinase (DAPK) is a calmodulin (CaM)-regulated serine/threonine protein kinase implicated in diverse apoptosis pathways, including those involved in neuronal cell death and tumour suppression. The requirement of DAPK catalytic activity for its proposed cell functions and the validation of protein kinases as therapeutic targets demand that DAPK be examined as a potential therapeutic target in human disease. The relevant placement of DAPK activity in apoptosis pathways is at an early stage of investigation, making its study as a therapeutic target tenuous. However, the current body of knowledge raises the possibility of DAPK as a therapeutic target for diseases characterised by rapid neurodegeneration, such as stroke or traumatic brain injury. The unmet need in these diseases is for an acute treatment schedule that might reduce neuronal loss. Bioavailable inhibitors of DAPK catalytic activity that target the central nervous system have a potential to fill this need. The development of such DAPK inhibitors is now feasible based on the recent emergence of enabling technology and knowledge. These include a quantitative and selective enzyme assay, a high resolution structure of the active catalytic domain and discovery of cell-permeable, low molecular weight inhibitors of CaM kinases that cross the blood-brain barrier. DAPK as a potential therapeutic target for cancer is less attractive due to the incomplete state of knowledge about DAPK and inherent limitations in drug development for the discovery of specific activators of genes downregulated by promoter hypermethylation. This article provides a brief summary of relevant research and the rationale that is at the foundation of this opinion.     

TANK-binding kinase 1 (TBK1): An emerging therapeutic target for drug discovery

Dysregulation of TANK-binding kinase 1 (TBK1) homeostasis leads to the occurrence and progression of many diseases, such as inflammation, autoimmune diseases, metabolic diseases, and cancer. Therefore, there is a need to develop TBK1 inhibitors as therapeutic agents. In this review, we highlight the diverse biological functions of TBK1 and summarize the promising small-molecule inhibitors of TBK1 that have the potential to be developed as therapeutic candidates.     

Raf kinase inhibitory protein (RKIP): A physiological regulator and future therapeutic target

Background: Raf kinase inhibitory protein (RKIP) belongs to the phosphatidylethanolamine binding protein (PEBP) family that is expressed in both prokaryotic and euakaryotic organisms. Objective: In this review, we discuss the role of RKIP as a modulator of signal transduction, the relationship of RKIP to other members of the PEBP family, and the role of RKIP in human health and disease. Results/conclusion: In mammals, RKIP regulates activation of MAPK, NF-κB and G protein coupled receptors (GPCRs). As a modulator of key signaling pathways, RKIP affects various cellular processes including cell differentiation, the cell cycle, apoptosis and cell migration. Emerging evidence suggests that RKIP is implicated in several human diseases or disorders, among them metastatic tumorigenesis and Alzheimer's disease.     

Leucine-rich repeat kinase 2 (LRRK2) as a potential therapeutic target in Parkinson's disease

Parkinson's disease (PD) is caused by the progressive degeneration of dopaminergic neurons in the substantia nigra. Although the etiology for most PD remains elusive, the identification of specific genetic defects in familial cases of PD and the signaling pathways governed by these genes has provided tremendous insight into PD pathogenesis. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are frequently found in familial and sporadic PD. Although current knowledge regarding the regulatory mechanisms of LRRK2 activation is limited, it is becoming increasingly evident that aberrant kinase activity of the pathologic mutants of LRRK2 is associated with neurodegeneration, suggesting that the kinase activity of LRRK2 is a potential therapeutic target. In addition, LRRK2 inhibitors might provide valuable tools to understand the pathophysiological and physiological roles of LRRK2 as well as the etiology of PD. We discuss here the potential and feasibility of targeting LRRK2 as a therapeutic strategy for PD.     

Ron receptor tyrosine kinase signaling as a therapeutic target

Introduction: Since its discovery nearly 20 years ago, the Ron receptor tyrosine kinase has been extensively studied. These studies have elucidated many of the major signaling pathways activated by Ron. In the context of the inflammation and cancer, studies have shown that Ron plays differential roles; Ron activation limits the inflammatory response, whereas in cancer, Ron activation is associated with increased metastases and poor prognosis.

Areas covered: This review discusses the current literature with regard to Ron signaling and consequences of its activation in cancer as well as its role in cancer therapy. Further, we discuss the mechanisms by which Ron influences the inflammatory response and its role in chronic inflammatory diseases. Finally, we discuss Ron's connection between chronic inflammation and progression to cancer.

Expert opinion: The complex nature of Ron's signaling paradigm necessitates additional studies to understand the pathways by which Ron is functioning and how these differ in inflammation and cancer. This will be vital to understanding the impact that Ron signaling has in disease states. Additional studies of targeted therapies, either alone or in conjunction with current therapies are needed to determine if inhibition of Ron signaling will provide long-term benefits to cancer patients.     

Ron receptor tyrosine kinase signaling as a therapeutic target

Introduction: Since its discovery nearly 20 years ago, the Ron receptor tyrosine kinase has been extensively studied. These studies have elucidated many of the major signaling pathways activated by Ron. In the context of the inflammation and cancer, studies have shown that Ron plays differential roles; Ron activation limits the inflammatory response, whereas in cancer, Ron activation is associated with increased metastases and poor prognosis. Areas covered: This review discusses the current literature with regard to Ron signaling and consequences of its activation in cancer as well as its role in cancer therapy. Further, we discuss the mechanisms by which Ron influences the inflammatory response and its role in chronic inflammatory diseases. Finally, we discuss Ron's connection between chronic inflammation and progression to cancer. Expert opinion: The complex nature of Ron's signaling paradigm necessitates additional studies to understand the pathways by which Ron is functioning and how these differ in inflammation and cancer. This will be vital to understanding the impact that Ron signaling has in disease states. Additional studies of targeted therapies, either alone or in conjunction with current therapies are needed to determine if inhibition of Ron signaling will provide long-term benefits to cancer patients.     

The kinase NIK as a therapeutic target in multiple myeloma

INTRODUCTION: Multiple myeloma (MM) is a neoplasm derived from B lymphocytes and often results in uncontrolled clonal expansion of antibody-secreting cells. While current treatments are able to prolong survival, MM remains incurable. Excessive NF-κB activity in MM contributes to tumor progression and survival. AREAS COVERED: The contribution of NF-κB-inducing kinase (NIK) to alternative NF-κB signaling, where it is the key kinase, and classical NF-κB signaling. Modulation of NIK by natural and chemical factors and current and potential therapies for MM that target NIK. EXPERT OPINION: Mutations affecting the activation of NIK have been identified in MM samples and cell lines, suggesting that NIK may be an important target for therapy of MM. NIK contributes to activation of both NF-κB pathways in MM, giving us the opportunity to limit two pathways contributing to oncogenic survival with a single therapeutic. Many of the mutations identified in MM cells result in the same outcome, hyperactive NIK, thus a single therapeutic may be effective in many patients even though they carry differing mutations. As NIK appears only to activate classical NF-κB when overexpressed, and in normal cells NIK levels are usually low, it is possible that therapeutics designed to limit the amount of NIK may not produce serious side effects in healthy cells.     

Lipoprotein(a) as a therapeutic target in cardiovascular disease

Introduction: Recent advances in genetics and epidemiology have once again thrust lipoprotein(a) (Lp(a)) into the clinical spotlight. Elevated plasma concentrations of Lp(a) are an independent, causal risk factor for coronary heart disease. The mechanisms underlying the pathogenicity of Lp(a) remain obscure, and uncertainty continues to surround the appropriate use of Lp(a) in the clinic.

Areas covered: We summarize the most recent findings on the biology and epidemiology of Lp(a), and use this as a platform to discuss strategies to lower plasma Lp(a) concentrations. The majority of the existing approaches are not Lp(a) specific since they also improve other aspects of the lipid profile. It is possible, however, that the unique characteristics of Lp(a) can be exploited to design therapeutics to specifically lower Lp(a).

Expert opinion: Lp(a) should be measured in selected patients, including those with a family history of cardiovascular disease (CVD), those with several risk factors for CVD and those who exhibit resistance to statins. Lp(a) lowering should not be the primary driver of choice of therapy, as it has not yet been established through randomized controlled trials that Lp(a) lowering per se has clinical benefit. The development of agents that specifically lower Lp(a) will allow interrogation of this question.     

Cyclin-dependent kinase 5 (Cdk5): a potential therapeutic target for the treatment of neurodegenerative diseases and diabetes mellitus

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine protein kinase, which forms active complexes with p35 or p39 expressed predominantly in neurons. Cdk5 is indispensable for the development of the central nervous system through regulation of neuronal migration. In mature neurons, Cdk5 has been implicated in various signaling transduction pathways, which contribute to functional neuronal activity. It has been widely accepted that aberrant Cdk5 activity induced by the conversion of p35 to p25 plays roles in the pathogenesis of neurodegenerative diseases. Cdk5 also contributes to adaptive changes in the brain related to drug addiction. Moreover, recent studies suggest that Cdk5 plays crucial roles in physiological functions in non-neuronal cells such as glucose-stimulated insulin secretion in pancreatic -cells. The present evidence indicates that Cdk5 might be a potential drug target for the treatment of neurodegenerative diseases, drug abuse and diabetes mellitus. This review focuses on the implication of Cdk5 in the signaling pathways of both neurodegenerative diseases and drug abuse, and the mechanism of Cdk5 involvement in insulin secretion. This review also discusses the possibility of using Cdk5 inhibitors as therapeutic drugs.