Platelet‐derived growth factor stimulates LAT1 gene expression in vascular smooth muscle: Role in cell growth

Abstract

Platelet-derived growth factor (PDGF) contributes to vascular disease by stimulating the growth of vascular smooth muscle cells (SMCs). Since amino acids are required for cell growth, the present study examined the effect of PDGF on system L amino acid transport, which is the predominant cellular pathway for the uptake of essential amino acids. System L amino acid transport was monitored by measuring the uptake of L-leucine. Treatment of SMCs with PDGF stimulated L-leucine transport in a concentration- and time-dependent manner, and this was associated with a selective increase in LAT1 mRNA and protein. PDGF failed to induce the expression of the other system L transport proteins, LAT2 and the heavy chain of the 4F2 cell surface antigen. The induction of LAT1 by PDGF was dependent on de novo RNA and protein synthesis and on mTOR activity. Serum, thrombin, and angiotensin II likewise stimulated L-leucine transport by inducing LAT1 expression. Inhibition of system L amino acid transport by the model substrate 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid blocked growth factor-mediated SMC proliferation and induced SMC apoptosis, whereas it had no effect on quiescent cells. These results demonstrate that growth factors stimulate system L amino acid transport by inducing LAT1 gene expression and that system L amino acid transport is essential for SMC proliferation and survival. The capacity of vascular mitogens to induce LAT1 expression may represent a basic mechanism by which tho acid transport * apoptosis

Protein Kinase C-Mediated Phosphorylation of a Single Serine Residue on the Rat Glial Glutamine Transporter SN1 Governs Its Membrane Trafficking

“…A hallmark of these two systems is that they are subject to extensive adaptive, hormonal, and osmotic regulation (Collarini and Oxender, 1987;Palacín et al, 1998). A nutrition signaling cascade that includes activation of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) has been shown to be important for induction of system A and system L activities (Peyrollier et al, 2000;Liu et al, 2004). In hepatocytes, insulin regulates expression of SN1 through the PI3K-mTor signaling cascade (Gu et al, 2005).…”

Potential Biomarker of L-type Amino Acid Transporter 1 in Breast Cancer Progression

“…It has been shown that LAT1 is overexpressed in some tumor tissues [34,35] and is actively involved in the proliferation of vascular smooth muscle cells [36]. In order to investigate whether or not LAT1 is involved in the proliferation of breast cancer cells, we employed BCH, a selective inhibitor of LAT1 [37,38], to inhibit the proliferation of malignant MDA-MB-231 cells.…”

Cell size reduction induced by inhibition of the mTOR/S6K-signaling pathway protects Jurkat cells from apoptosis

“…[1][2][3] In this model, signals arising from the extracellular milieu as growth factors 4,5 and nutrient availability, 6,7 from changes of transporter activity at the cell membrane 8,9 or directly from intracellular metabolic changes affecting internal amino-acid levels [9][10][11][12][13] and ATP availability [14][15][16] all feed into mTOR which, by integrating this information, couples the cellular metabolic state to downstream targets that modulates rates of translation and thereby cell mass and number. 17 mTOR, also known as FKBP12-rapamycin-associated protein (FRAP) 18 /rapamycin and FKBP12 target (RAFT-1) 19 with its putative raptor, 20,21 G protein b-subunit-like protein (GbL) 22 and tuberous sclerosis complex (Tsc)/Ras-related protein (Rheb) 3,12 regulators, modulate the phosphorylation state of p70 ribosomal S6 kinase 1 (S6K1) and other downstream effectors.…”