MAP Kinase Phosphatase As a Locus of Flexibility in a Mitogen-Activated Protein Kinase Signaling Network

Abstract

Intracellular signaling networks receive and process information to control cellular machines. The mitogen-activated protein kinase (MAPK) 1,2/protein kinase C (PKC) system is one such network that regulates many cellular machines, including the cell cycle machinery and autocrine/paracrine factor synthesizing machinery. We used a combination of computational analysis and experiments in mouse NIH-3T3 fibroblasts to understand the design principles of this controller network. We find that the growth factor-stimulated signaling network containing MAPK 1, 2/PKC can operate with one (monostable) or two (bistable) stable states. At low concentrations of MAPK phosphatase, the system exhibits bistable behavior, such that brief stimulus results in sustained MAPK activation. The MAPK-induced increase in the amounts of MAPK phosphatase eliminates the prolonged response capability and moves the network to a monostable state, in which it behaves as a proportional response system responding acutely to stimulus. Thus, the MAPK 1, 2/PKC controller network is flexibly designed, and MAPK phosphatase may be critical for this flexible response.

Initiation of Oligodendrocyte Progenitor Cell Migration by a PDGF-A Activated Extracellular Regulated Kinase (ERK) Signaling Pathway

“…The activation of cPLA 2 results in increased arachidonic acid (AA) release, which in turn, activates protein kinase C (PKC) [14]. AA activation of PKC leads to the phosphorylation of Raf, forming a positive feedback loop within the ERK cascade.…”

“…AA activation of PKC leads to the phosphorylation of Raf, forming a positive feedback loop within the ERK cascade. We used arachidonyltrifluoromethyl ketone (AACOCF 3 ) to inhibit cPLA 2 activation [14]. At 10 μM as previously demonstrated to block cPLA 2 activation [14], AACOCF 3 reduced OP migration 27.5% at 72 h when stimulated from a 30 min exposure to PDGF-A, compared to controls (588 ± 71 μm in the presence of AACOCF 3 as compared to 811 ± 39 μm; n = 5 with 4-6 replicates; P < 0.01) (Fig.…”

“…Phosphorylation of ERK2 (p42 MAPK ) activates cPLA 2 [33]. The activation of cPLA 2 results in increased AA release, which in turn, activates PKC [14,47]. PKC stimulates the ERK pathway through activation of Raf [14].…”

Exploring the cell's network with molecular imaging

“…While there are certainly linear pathways, even these pathways often interact to form subnetworks (47,57). The resultant behavior may not be intuitive and requires not only a knowledge of network topology, but also quantification of the biochemical reactions (69). In the cell's growth-signaling network resides an important integrating pathway, the Ras-Raf-mitogen-activated protein kinase (MAPK) mitogenic cascade.…”

“…This subnetwork signals the nucleus from the cytoplasm and is dysregulated in up to 25% of tumors (57,70). The output of the MAPK system regulates many cellular functions including the cell cycle (69). It exhibits nonintuitive emergent behavior in response to its input producing either a proportional output or an all or none output.…”