期刊
IMMUNOLOGY LETTERS
卷 196, 期 -, 页码 74-79出版社
ELSEVIER
DOI: 10.1016/j.imlet.2018.01.015
关键词
mTOR kinase; Migration; Chronic lymphocytic leukemia; AKT; Lymphocytosis
类别
资金
- Medical Research Council UK (MRC) 'Mechanism of Disease' grant
- AstraZeneca [MR/K014854/1]
- Bloodwise [15041]
- Kay Kendall Leukaemia Fund UK (KKLF) Clinical training fellowship [KKL838]
- Medical Research Council [MR/K014854/1] Funding Source: researchfish
- MRC [MR/K014854/1] Funding Source: UKRI
Mechanistic target for rapamycin (mTOR) is a serine/threonine protein kinase that forms two distinct complexes mTORC1 and mTORC2, integrating mitogen and nutrient signals to regulate cell survival and proliferation; processes which are commonly deregulated in human cancers. mTORC1 and mTORC2 have divergent molecular associations and cellular functions: mTORC1 regulates in mRNA translation and protein synthesis, while mTORC2 is involved in the regulation of cellular survival and metabolism. Through AKT phosphorylation/activation, mTORC2 has also been reported to regulate cell migration. Recent attention has focused on the aberrant activation of the PI3K/mTOR pathway in B cell malignancies and there is growing evidence for its involvement in disease pathogenesis, due to its location downstream of other established novel drug targets that intercept B cell receptor (BCR) signals. Shared pharmacological features of BCR signal inhibitors include a striking lymphocyte redistribution effect whereby patients experience a sharp increase in lymphocyte count on initiation of therapy followed by a steady decline. Chronic lymphocytic leukemia (CLL) serves as a paradigm for migration studies as lymphocytes are among the most widely travelled cells in the body, a product of their role in immunological surveillance. The subversion of normal lymphocyte movement in CLL is being elucidated; this review aims to describe the migration impairment which occurs as part of the wider context of cancer cell migration defects, with a focus on the role of mTOR in mediating migration effects downstream of BCR ligation and other microenvironmental signals.
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