Integrin-mediated signalling through the MAP-kinase pathway

Abstract

The mitogen activated protein (MAP) kinase cascade, leading to extracellular-regulated kinase (ERK) activation, is a key regulator of cell growth and proliferation. The effects of ERK are mediated by differences in ERK signalling dynamics, including magnitude and duration. In vivo, ERK signalling is stimulated by both growth factors and adhesion signals. A model for adhesionmediated ERK activation is presented. Outputs of the model such as ERK and FAK activation, as well as responses to different ligand densities, are compared with published experimental data. The model then serves as a basis for understanding how adhesion may contribute to ERK signalling through changes in the dynamics of focal adhesion kinase activation. The main parameters influencing ERK are determined through screening analyses and parameter variation. With these parameters, key points in the pathway that give rise to changes in downstream signalling dynamics are identified. In particular, oncogenic Raf and Ras promote cell growth by increasing the magnitude and duration, respectively, of ERK activity. This material is posted here with permission of the IEEE. Such permission of the IEEE does not in any way imply IEEE endorsement of any of the University of Pennsylvania's products or services. Internal or personal use of this material is permitted. However, permission to reprint/republish this material for advertising or promotional purposes or for creating new collective works for resale or redistribution must be obtained from the IEEE by writing to pubs-permissions@ieee.org. By choosing to view this document, you agree to all provisions of the copyright laws protecting it.This journal article is available at ScholarlyCommons: http://repository.upenn.edu/be_papers/104Integrin-mediated signalling through the MAP-kinase pathway K.L. Yee, V.M. Weaver and D.A. HammerAbstract: The mitogen activated protein (MAP) kinase cascade, leading to extracellular-regulated kinase (ERK) activation, is a key regulator of cell growth and proliferation. The effects of ERK are mediated by differences in ERK signalling dynamics, including magnitude and duration. In vivo, ERK signalling is stimulated by both growth factors and adhesion signals. A model for adhesionmediated ERK activation is presented. Outputs of the model such as ERK and FAK activation, as well as responses to different ligand densities, are compared with published experimental data. The model then serves as a basis for understanding how adhesion may contribute to ERK signalling through changes in the dynamics of focal adhesion kinase activation. The main parameters influencing ERK are determined through screening analyses and parameter variation. With these parameters, key points in the pathway that give rise to changes in downstream signalling dynamics are identified. In particular, oncogenic Raf and Ras promote cell growth by increasing the magnitude and duration, respectively, of ERK activity.

Low-intensity Ultrasound Increases FAK, ERK-1/2, and IRS-1 Expression of Intact Rat Bones in a Noncumulative Manner

“…One mechanical stimulation increases P-FAK and P-ERK-1/2 for 4 hours [4,14,26,36], whereas our long-term LIPUS not only increased P-FAK and P-ERK-1/2, but also prolonged their activation for 15 hours at 7 and 14 days (only ERK-1/2). P-FAK and P-ERK-1/2 peaks coincided with their expression peaks, supporting the observation that sustained P-FAK and P-ERK-1/2 elevation are proportional to the elevation of their expression [46]. Nevertheless, P-FAK was not detected at 21 days, suggesting the LIPUS regulatory mechanism may act more on FAK activity than on its expression.…”

“…Probably, other ERK-1/2 upstream proteins, not FAK, have exhibited augmented activation at 14 days and increased P-ERK-1/2; and the mechanisms by which LIPUS increases FAK and ERK-1/2 expression are different, both regulated by a major regulatory mechanism. Studies suggest sustained P-ERK-1/2 more effectively regulates nuclear reactions than intermittent P-ERK-1/2 [11,27,32,46]. How long-term LIPUS induced sustained increased P-FAK and P-ERK-1/2 is unknown.…”

Optimal Intensity Shock Wave Promotes the Adhesion and Migration of Rat Osteoblasts via Integrin β1-mediated Expression of Phosphorylated Focal Adhesion Kinase

“…Another possible explanation for the discrepancy is that ESW could activate Shc first (Fig. 8) and enhance the ERK1/2 phosphorylation (48,49). Additional studies would be required to confirm these speculations.…”

Mechanisms of adrenal gland growth: signal integration by extracellular signal regulated kinases1/2

“…It is clear that many GPCR agonists (angiotensin, VIP, vasopressin) but also environmental or psychosocial factors induce cell proliferation by direct activation of ERK1/2 or in a synergistic manner with RTKs (Rozengurt 2007). In addition to RTKs and GPCRs also cytokine receptors e.g., the GH receptor (Brooks et al 2008) and integrins ( Yee et al 2008) impact on ERK1/2. From the multiple activation of ERK1/2 in the different adrenal compartments we may assume that a large number of signals is tracking ERK1/2 also in the adrenal gland suggesting a role in adrenal growth and function, which hardly can be overestimated.…”