FBXL7 下调 AURKA 在细胞有丝分裂进入期和早期有丝分裂期间
中文名称
通路描述
AURKA 蛋白水平在细胞有丝分裂进入期和早期有丝分裂期间可通过 SCF-FBXL7 E3 泛素连接酶复合物（由 SKP1、CUL1、RBX1 和 FBXL7 亚基组成）的作用而降低。FBXL7 是 SCF-FBXL7 复合物的底物识别亚基，与中心体结合的 AURKA 结合，促进其泛素化及蛋白酶体介导的降解。FBXL7 的过表达会导致 G2/M 细胞周期阻滞和凋亡（Coon et al. 2011）。FBXL7 蛋白水平可通过 SCF-FBXL18 E3 泛素连接酶复合物的作用而下调，该复合物由 SKP1、CUL1、RBX1 和底物识别亚基 FBXL18 组成。FBXL18 结合 FBXL7 的 FQ 基序，将其靶向泛素化并介导蛋白酶体降解，从而抵消其促凋亡活性（Liu et al. 2015）。FBXL7 由 FBXL18 下调的细胞周期阶段依赖性尚不清楚。
英文描述
Signaling by ALK The anaplastic lymphoma kinase (ALK) is a transmembrane receptor tyrosine kinase that, along with related receptor LTK (leukocyte tyrosine kinase receptor) is a member of the insulin receptor superfamily (Iwahara et al, 1997). ALK was discovered as an oncogene in anaplastic large cell lymphomas (ALCLs), but also plays an oncogenic role in other cancer types, such as non-small-cell lung cancer (NSCLC), inflammatory myofibroblastic tumours (IMT), melanoma, neuroblastoma and glioblastoma. In cancer, the chromosomal region encoding ALK frequently undergoes genomic rearrangements, resulting in the formation of ALK fusion proteins, such as NPMâALK (the result of a translocation event, t(2;5)(p23;q35) which is predominant in ALCL) and EML4âALK (an inversion event on chromosome 2) (Morris et al, 1994; Couts et al, 2018). These fusion proteins consist of the Câterminal region of ALK, encompassing the kinase domain and the effector protein binding domain (with loss of the transmembrane domain), while the Nâterminus of the fusion protein contains the dimerization domain of the partner gene. Fusion proteins of ALK are therefore capable of ligandâindependent dimerization, resulting in constitutive ALK signaling (reviewed in Duyster et al, 2001; Chiarle et al, 2008; Della Corte et al, 2018; Hallberg and Palmer, 2013; Hallberg and Palmer, 2016; Janoueix-Larousey et al, 2018; Ducray et al, 2019). Additionally, amplification of ALK and/or point mutations leading to its constitutive activation have been detected in neuroblastoma (reviewed in McDuff et al, 2011).
Many of the functional studies on ALK have been conducted in the context of oncogenic forms of the protein. In contrast, fewer studies have been conducted on the wild type protein under normal physiological conditions, and indeed, ALK was initially classed as an orphan receptor with no identified ligand. Two small heparin-binding growth factors, pleiotrophin (PTN) and midkine (MDK), were initially identified as potential ligands however subsequent studies failed to support this (Stoica et al, 2001; Stoica et al, 2002; Mathivet et al, 2007; Moog-Lutz et al, 2005; Motegi et al, 2004; reviewed in Wellstein et al, 2012; Winkler et al, 2014; Herradon and Perez-Garcia, 2014). More recently, ALKAL1 and ALKAL2 (also known as FAM150A and FAM150B) have been identified as ligands for both ALK and the related LTK receptor, albeit with differing potencies (Zhang et al, 2014; Guan et al, 2015; Reshetnyak et al, 2015; Reshetnyak et al, 2018; Fadeev et al, 2018; Reshetnyak et al, 2021; De Munck et al, 2021; Borenas et al, 2021; reviewed in Hallberg and Palmer, 2016). Whereas LTK receptor is potently activated by both ALKAL1 and ALKAL2, ALK is only weakly stimulated by ALKAL1 (Reshetnyak et al, 2015; Reshetnyak et al, 2018). Ligand binding induces the dimerization of the receptor and transautophosphorylation, resulting in a fully activated receptor that triggers downstream signaling cascades such as RAS, PI3K and IRS1 signaling. ALK may also undergo ligand-independent activation through RPTPB/RPTPZ (Deuel et al, 2013).
ALK is mainly expressed in the developing central and peripheral nervous system and plays a role in differentiation during development (Souttou et al, 2001; Gouzi et al, 2005; Degoutin et al, 2007). In Drosophila and mice, ALK is a thinness gene involved in the resistance to weight gain (Orthofer et al, 2020). Through activation of STAT3 targets, ALK also appears to play a role in response to ethanol (Hamada et al, 2021).
Many of the functional studies on ALK have been conducted in the context of oncogenic forms of the protein. In contrast, fewer studies have been conducted on the wild type protein under normal physiological conditions, and indeed, ALK was initially classed as an orphan receptor with no identified ligand. Two small heparin-binding growth factors, pleiotrophin (PTN) and midkine (MDK), were initially identified as potential ligands however subsequent studies failed to support this (Stoica et al, 2001; Stoica et al, 2002; Mathivet et al, 2007; Moog-Lutz et al, 2005; Motegi et al, 2004; reviewed in Wellstein et al, 2012; Winkler et al, 2014; Herradon and Perez-Garcia, 2014). More recently, ALKAL1 and ALKAL2 (also known as FAM150A and FAM150B) have been identified as ligands for both ALK and the related LTK receptor, albeit with differing potencies (Zhang et al, 2014; Guan et al, 2015; Reshetnyak et al, 2015; Reshetnyak et al, 2018; Fadeev et al, 2018; Reshetnyak et al, 2021; De Munck et al, 2021; Borenas et al, 2021; reviewed in Hallberg and Palmer, 2016). Whereas LTK receptor is potently activated by both ALKAL1 and ALKAL2, ALK is only weakly stimulated by ALKAL1 (Reshetnyak et al, 2015; Reshetnyak et al, 2018). Ligand binding induces the dimerization of the receptor and transautophosphorylation, resulting in a fully activated receptor that triggers downstream signaling cascades such as RAS, PI3K and IRS1 signaling. ALK may also undergo ligand-independent activation through RPTPB/RPTPZ (Deuel et al, 2013).
ALK is mainly expressed in the developing central and peripheral nervous system and plays a role in differentiation during development (Souttou et al, 2001; Gouzi et al, 2005; Degoutin et al, 2007). In Drosophila and mice, ALK is a thinness gene involved in the resistance to weight gain (Orthofer et al, 2020). Through activation of STAT3 targets, ALK also appears to play a role in response to ethanol (Hamada et al, 2021).
所含基因
18 个基因