PYK2 signaling is required for PDGF-dependent vascular smooth muscle cell proliferation
- 1 July 2011
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 301 (1), C242-C251
- https://doi.org/10.1152/ajpcell.00315.2010
Abstract
Aberrant vascular smooth muscle cell (VSMC) growth is associated with many vascular diseases including atherosclerosis, hypertension, and restenosis. Platelet-derived growth factor-BB (PDGF) induces VSMC proliferation through control of cell cycle progression and protein and DNA synthesis. Multiple signaling cascades control VSMC growth, including members of the mitogen-activated protein kinase (MAPK) family as well as phosphatidylinositol 3-kinase (PI3K) and its downstream effector AKT/protein kinase B (PKB). Little is known about how these signals are integrated by mitogens and whether there are common receptor-proximal signaling control points that synchronize the execution of physiological growth functions. The nonreceptor proline-rich tyrosine kinase 2 (PYK2) is activated by a variety of growth factors and G protein receptor agonists in VSMC and lies upstream of both PI3K and MAPK cascades. The present study investigated the role of PYK2 in PDGF signaling in cultured rat aortic VSMC. PYK2 downregulation attenuated PDGF-dependent protein and DNA synthesis, which correlated with inhibition of AKT and extracellular signal-regulated kinases 1 and 2 (ERK1/2) but not p38 MAPK activation. Inhibition of PDGF-dependent protein kinase B (AKT) and ERK1/2 signaling by inhibitors of upstream kinases PI3K and MEK, respectively, as well as downregulation of PYK2 resulted in modulation of the G1/S phase of the cell cycle through inhibition of retinoblastoma protein (Rb) phosphorylation and cyclin D1expression, as well as p27Kipupregulation. Cell division kinase 2 (cdc2) phosphorylation at G2/M was also contingent on PDGF-dependent PI3K-AKT and ERK1/2 signaling. These data suggest that PYK2 is an important upstream mediator in PDGF-dependent signaling cascades that regulate VSMC proliferation.Keywords
This publication has 56 references indexed in Scilit:
- Pyk2 Inhibition of p53 as an Adaptive and Intrinsic Mechanism Facilitating Cell Proliferation and SurvivalPublished by Elsevier BV ,2010
- AKT/PKB Signaling: Navigating DownstreamCell, 2007
- The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transitionOncogene, 2007
- Basic Mechanisms of Oxidative Stress and Reactive Oxygen Species in Cardiovascular InjuryTrends in Cardiovascular Medicine, 2007
- The NR4A Orphan Nuclear Receptor NOR1 Is Induced by Platelet-derived Growth Factor and Mediates Vascular Smooth Muscle Cell ProliferationJournal of Biological Chemistry, 2006
- The Cytoplasmic Tyrosine Kinase Pyk2 as a Novel Effector of Fibroblast Growth Factor Receptor 3 ActivationPublished by Elsevier BV ,2004
- Different Growth Properties of Neointimal and Medial Smooth Muscle Cells in Response to Growth FactorsJournal of Vascular Research, 2003
- Proprotein Convertase PC5 Regulation by PDGF-BB Involves PI3-Kinase/p70 s6 -Kinase Activation in Vascular Smooth Muscle CellsHypertension, 2002
- Differential Regulation of P27Kip1 Expression by Mitogenic and Hypertrophic FactorsThe Journal of cell biology, 2000
- Role of Calcium-Sensitive Tyrosine Kinase Pyk2/CAKβ/RAFTK in Angiotensin II–Induced Ras/ERK SignalingHypertension, 1998