The dual-specificity MAPK phosphatase MKP-1/CL100/DUSP1 is an inducible nuclear protein controlled by p44/42 MAPK (ERK1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain ERK activation by triggering MKP-1 proteolysis. Active ERK2 docking to the DEF motif (FXFP, residues 339 -342) of N-terminally truncated MKP-1 in vitro initiated phosphorylation at the

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Sustained extracellular signal-regulated kinase 1/2 (ERK1/2) activation does not always correlate with its upstream Ras-Raf-mitogen-activated protein kinase kinase 1/2 (MKK1/2) signal cascade in cancer cells, and the mechanism remains elusive. Here we report a novel mechanism by which sustained ERK1/2 activation is established. We demonstrate that Pb(II), a carcinogenic metal, persistently induces ERK1/2 activity in CL3 human lung cancer cells and that Ras-Raf-MKK1/2 signaling cannot fully account for such activation. It is intriguing that Pb(II) treatment reduces mitogenactivated protein kinase phosphatase 1 (MKP-1) protein levels in time-and dose-dependent manners, which correlates with sustained ERK1/2 activation, and that Pb(II) also induces mRNA and de novo protein synthesis of MKP-1. In Pb ( Members of the family of mitogen-activated protein kinase (MAPK) 1 proteins are vital intracellular signaling components that become phosphorylated and activated in response to a wide diversity of extracellular stimuli, including growth factors, cytokines, and environmental stresses (reviewed in Refs. 1-5). MAPKs are activated through a three-kinase module composed of a MAPK, a MAPK kinase (MKK), and a MKK kinase (MKKK). These MAPK modules are connected to cell surface receptors and activated via interaction with a family of small GTPases and MKKK kinases. Activated MAPKs phosphorylate many substrates, including cytoskeletal proteins, other kinases, phosphatases, enzymes, and transcription factors, thereby orchestrating several cellular alterations including proliferation, differentiation, survival, and apoptosis. The duration and strength of MAPK activation also affects these biological outcomes. Three major MAPK subfamilies have been extensively studied, i.e. the extracellular signal-regulated kinases (ERK1/2), the c-Jun N-terminal kinases (JNKs), and the p38 kinases. Activation of a particular MAPK signal must be controlled with high specificity and efficiency to achieve precise physiological regulation. The recent discovery of specific docking sites among the members of the MAPK cascades provide a mechanism that explains how specific and efficient signaling is established. For instance, a cluster of positively charged amino acids followed by an LXL motif called the D domain (or the kinase interaction motif, KIM) has been identified in MKKs, MAPK phosphatases (MKPs), and several MAPK substrates (6 -8). The D domain binds specifically to an acidic domain (common docking domain) within a docking groove of MAPKs (6 -8). Another docking site found in many ERK substrates is called the DEF motif (docking site for ERK, FXFP) (8, 9). These docking interactions facilitate phosphorylation of substrates by MAPKs on specific Ser or Thr residues followed by a Pro residue ((S/T)P sites).The small GTPase, MKKK, and MKK in the ERK pathway are known to be Ras, Raf, and MKK1/2, respectively (1-5). Activation of ERK1/2 requires a dual-phosphorylation by MKK1/2 on the Thr and Tyr residues of TEY sites within the activation loop, wherea...

In this paper, we investigate a mobicast, also called a mobile geocast, problem in three-dimensional (3-D) underwater sensor networks (USNs), which aims to overcome the hole problem and minimizes the energy consumption of the sensor nodes while maximizing the data collection. In this paper, all underwater sensor nodes are randomly distributed in a 3-D underwater environment in the sea to form a 3-D USN. Considered a mobile sink or an autonomous underwater vehicle (AUV), all possible sensor nodes near the AUV form a 3-D geographic zone called a 3-D zone of reference (3-D ZOR). The AUV travels a user-defined route and continuously collects data from sensor nodes within a series of 3-D ZORs at different times. The main problem is how to efficiently collect data from sensor nodes within a 3-D ZOR while those sensor nodes are usually in sleep mode for a long period. The routing protocol relies on two phases: the first phase consists of collecting data within a 3-D ZOR, and the second phase consists of waking up those sensor nodes in the next 3-D ZOR to be queried while trying to avoid topology holes. To save power, only sensor nodes in a 3-D ZOR are notified to enter the active mode in order to deliver sensed results to the AUV. The specific characteristics of USNs, including low communication bandwidth, large propagation delay, and ocean current, are significantly different from wireless sensor networks. To consider the characteristics of USNs, a new mobicast routing protocol is developed in 3-D USNs. The key design challenge is to develop a power-saving mobicast protocol in 3-D USNs to overcome the unpredictable 3-D hole problem. To solve the hole problem, an "apple slice" technique is used to build multiple segments to surround the hole and to assure routing path continuity. Finally, performance analysis is derived, and simulation results illustrate the performance improvement in successful delivery rate, power consumption, and message overhead.

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