Role of scaffolds in MAP kinase pathway specificity revealed by custom design of pathway-dedicated signaling proteins

Harris, Kendra; Lamson, Rachel E.; Nelson, Bryce; Hughes, Timothy R.; Marton, Matthew J.; Roberts, Christopher J.; Boone, Charles; Pryciak, Peter M.

doi:10.1016/s0960-9822(01)00567-x

Cited by 108 publications

(83 citation statements)

References 43 publications

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“…Distinct regions of Ste5 also bind to Ste7 MEK and to the MAPKs. Here, Ste5 is thought to function as a scaffold, co-localizing, sequestering and organizing the component protein kinases of the mating MAPK cascade, thus enhancing signal transmission from MEKK to MEK to MAPK [19,38,49,57,110,118,128,146].…”

Section: The Map Kinase Cascade-overviewmentioning

confidence: 99%

A walk-through of the yeast mating pheromone response pathway

2004

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Section: The Map Kinase Cascade-overviewmentioning

confidence: 99%

A walk-through of the yeast mating pheromone response pathway

2004

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“…Similar use of artificial scaffolds has been previously shown to direct MAPK signalling in yeast. 36,37 To date, no MAPK scaffold proteins have been characterised that direct signalling to mitochondria. 30 Thus, the membrane-associated complex that we observe in detached cells may contain novel p38MAPK-interacting proteins that direct a specific stress response to control apoptosis commitment.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis commitment and activation of mitochondrial Bax during anoikis is regulated by p38MAPK

et al. 2009

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Most cells undergo apoptosis through the intrinsic pathway. This is dependent on mitochondrial outer membrane permeabilisation (MOMP), which is mediated by the pro-apoptotic Bcl-2 family proteins, Bax and Bak. During apoptosis, Bax translocates from the cytosol to the outer mitochondrial membrane (OMM), wherein it contributes to the formation of pores to release cytochrome-c. However, it remains unclear whether Bax translocation is sufficient to bring about MOMP or whether Bax requires further signals on the OMM to be fully activated. We have previously shown that during mammary epithelial cell anoikis, Bax translocation does not commit cells to MOMP and detached cells are rescued if survival signals from the extracellular matrix (ECM) are restored. These findings implied that a second signal is required for mitochondrial Bax to fully activate and cause MOMP. We now identify p38MAPK (mitogen-activated protein kinase) as this necessary signal to activate Bax after its translocation to mitochondria. The inhibition of p38MAPK did not prevent Bax translocation, but its activity was required for mitochondrial Bax to bring about MOMP. p38MAPK was activated and recruited to a high molecular weight mitochondrial complex after loss of ECM attachment. Artificially targeting p38MAPK to the OMM increased the kinetics of anoikis, supporting a requirement for its mitochondrial localisation to regulate Bax activation and drive commitment to apoptosis. Metazoan cells are pre-programmed to undergo apoptosis in response to becoming damaged or losing essential survival signals. Apoptosis in response to these cellular stresses is initiated through the intrinsic, or mitochondrial, pathway. 1 During intrinsic apoptosis, mitochondrial outer membrane permeabilisation (MOMP) results in the release of proteins, such as cytochrome-c and second mitochondrial activator of caspases (Smac)/Diablo, which activate the caspases to drive cell death. The release of cytochrome-c and Smac/Diablo is an extremely rapid event, with mitochondria throughout the cell releasing their contents within a few minutes of MOMP first commencing. 2,3 The resulting activation of caspases occurs immediately and cell death is complete within a few minutes. After MOMP, cells rapidly lose viability, even if caspase activation is inhibited. Thus, MOMP represents a point at which cells cannot be rescued from an apoptotic fate.The Bcl-2 family of proteins regulates MOMP. 4 These are characterised by a number of shared regions of sequence homology, the Bcl-2 Homology (BH) domains. Pro-survival members, such as Bcl-2 and Bcl-X L , share BH-domains 1-4. In contrast, the pro-apoptotic proteins, Bax and Bak, only posses BH-domains 1, 2 and 3. A third group of Bcl-2 proteins are the BH3-only proteins, which function by sensing survival and stress signals, and transmit these to the pro-and antiapoptotic multi-domain proteins. 5 The multi-domain proapoptotic proteins, Bax and Bak, are expressed in virtually all tissues, and are absolutely required for MOMP to occur. 6 Cells deriv...

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“…To illustrate this approach, we first approximate the integrand (27) using a r − 1th order Lagrange polynomial at a set of interpolation points t n+1 , t n ,…, t n+2−r : (28) Then (12) becomes (29) A first order implicit approximation to (τ) of the form (30) leads to a first order implicit scheme (31) A second order implicit approximation to (τ), (32) leads to a second order implicit scheme (33) Like the implicit ETD methods based on the non-compact representation, the nonlinear function of U n+1 in the compact implicit ETD (33) is also multiplied by terms involving the approximated differential operators and their exponentials. This non-local coupling makes the implicit ETD method inefficient.…”

Section: Two-dimensionsmentioning

confidence: 99%

“…Scaffold usually binds dynamically to two or more consecutively-acting components of a signaling cascade. Experimental work suggests that scaffolds may promote signal transmission by tethering consecutively acting kinases near each other [31,32]. However, it has also been experimentally observed that some scaffold inhibit signaling when over-expressed [33][34][35].…”

Section: 22mentioning

confidence: 99%

Compact integration factor methods in high spatial dimensions

Nie

Wan

Zhang

et al. 2008

Journal of Computational Physics

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The dominant cost for integration factor (IF) or exponential time differencing (ETD) methods is the repeated vector-matrix multiplications involving exponentials of discretization matrices of differential operators. Although the discretization matrices usually are sparse, their exponentials are not, unless the discretization matrices are diagonal. For example, a two-dimensional system of N × N spatial points, the exponential matrix is of a size of N 2 × N 2 based on direct representations. The vector-matrix multiplication is of O(N 4 ), and the storage of such matrix is usually prohibitive even for a moderate size N. In this paper, we introduce a compact representation of the discretized differential operators for the IF and ETD methods in both two-and three-dimensions. In this approach, the storage and CPU cost are significantly reduced for both IF and ETD methods such that the use of this type of methods becomes possible and attractive for two-or three-dimensional systems. For the case of two-dimensional systems, the required storage and CPU cost are reduced to O(N 2 ) and O(N 3 ), respectively. The improvement on three-dimensional systems is even more significant. We analyze and apply this technique to a class of semi-implicit integration factor method recently developed for stiff reaction-diffusion equations. Direct simulations on test equations along with applications to a morphogen system in two-dimensions and an intra-cellular signaling system in three-dimensions demonstrate an excellent efficiency of the new approach.

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Role of scaffolds in MAP kinase pathway specificity revealed by custom design of pathway-dedicated signaling proteins

Cited by 108 publications

References 43 publications

A walk-through of the yeast mating pheromone response pathway

A walk-through of the yeast mating pheromone response pathway

Apoptosis commitment and activation of mitochondrial Bax during anoikis is regulated by p38MAPK

Compact integration factor methods in high spatial dimensions

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