The role of mTOR-mediated signaling in the regulation of cellular migration

Abstract

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.

The knocking down of the oncoprotein Golgi phosphoprotein 3 in T98G cells of glioblastoma multiforme disrupts cell migration by affecting focal adhesion dynamics in a focal adhesion kinase-dependent manner

“…Thus, it has been found that abnormalities in RhoA function could lead to cancer progression through metastatic growth [79]. On the other hand, there are a number of possibilities in which the mTOR-signaling pathway participates in the regulation of malignant cell migration [80], which include the activation of RhoA [81]. How the overexpression of GOLPH3 activates RhoA and the mTOR-signaling pathway is unknown.…”

U2AF65 enhances milk synthesis and growth of bovine mammary epithelial cells by positively regulating the mTOR‐SREBP‐1c signalling pathway

“…Here, we propose that extracellular stimuli (Met, Leu, β-estradiol, migration, 22 and tumour progression. 23 Moreover, recent studies have indicated that the regulation of protein translation and cell proliferation by amino acids and hormones via the mTOR signalling pathway is a crucial determinant of milk production in BMECs.…”

Adolescent-onset and adult-onset schizophrenia: reduced ribosomal protein expression via mTOR signalling in patient-derived olfactory cells

“…Taken together these reports suggest that mTOR function and hence protein synthesis may be less stable in schizophrenia, varying with cell type and age. This instability could affect brain development and adult brain function because mTOR regulates focal adhesion and actin cytoskeleton formation to affect cell adhesion, axon outgrowth and synaptic stability [43][44][45][46] . Our findings of the same dysregulated protein synthesis pathways in adolescent-and adult-onset patient cells places our findings at the heart of brain development by providing a site where schizophreniaassociated dysregulation could affect the growth of axons and dendrites and alter the trajectory of brain development.…”