Academic journal article Genetics

Domain Specificity of MAP3K Family Members, MLK and Tak1, for JNK Signaling in Drosophila

Academic journal article Genetics

Domain Specificity of MAP3K Family Members, MLK and Tak1, for JNK Signaling in Drosophila

Article excerpt

PROTEIN kinases are common transducers of information within cells. Indeed, reversible phosphorylation of sub- strates, by the opposing activities of kinases and phospha- tases, is a major currency in cells forming the basis for information relay in many signaling pathways, ultimately transforming cell behavior in response to a changing envi- ronment. Unregulated kinase activity, however, has been implicated in numerous diseases of medical concern, notably cancer. One family in particular, the mitogen-activated pro- tein kinases (MAPKs), composed of ERK, p38, and JNK en- zymes, are central to a vast array of cellular and pathological processes (Chang and Karin 2001; Johnson and Nakamura 2007; Wagner and Nebreda 2009; Keshet and Seger 2010; Sabapathy 2012). Converging on the activation of MAPKs are typically two additional levels of kinases within a hier- archical three-tiered core, namely the MAPK kinases or MAP2Ks, and their activators, the MAPK kinase kinases, or MAP3Ks. While MAPK enzymes have been extensively stud- ied at biochemical, structural, and physiological levels, the MAP3Ks are less well understood, more diverse, and greater in number. For example, in mammals there exist at least 20 different MAP3K family members, 14 of which impinge downstream upon three JNK stress-activated protein kinases (SAPKs) (Cuevas et al. 2007; Johnson and Nakamura 2007; Craig et al. 2008). From an evolutionary standpoint, the diversity of MAP3Ks may allow cells to respond to a greater breadth of stimuli or with greater sensitivity to discrete sig- nals. Emerging evidence suggests that MAP3Ks can work selectively or cooperatively downstream of different signals to tune a MAPK network response (Chen et al. 2002; Cronan et al. 2012). The selective function of MAP3Ks can presumably be harnessed to provide specific alternative therapeutic tar- gets for MAPK pathway-associated disease intervention. On the other hand, if MAP3Ks act cooperatively to fine tune a response, then targeting individual members could result in minimal efficacy. Thus, elucidation of the context-dependent functions and mechanisms of signaling specificity among MAP3K proteins is the focus of current research.

Context-dependent influences, like environmental, cellu- lar, developmental, or spatial influences, are pervasive in tuning signaling networks. As such, a major challenge is to understand the molecular mechanisms by which context imparts distinct properties to a system. Recent work has provided some mechanistic insight. For example, within a single cell, related kinases might avoid inappropriate crosstalk by deploying nonoverlapping substrates or by compartmentalization of their function in cellular space or time (Alexander et al. 2011). Considering the conserved three-tier kinase organization within the MAPK pathways, the core pathway may incorporate distinct upstream trans- ducers, as is the case with the diversity of MAP3K proteins, to shift the outcome of signaling in response to distinct stim- uli. Two general approaches to the challenge of identifying context-dependent influences on signaling have been ap- plied: first, to alter the context of a constant set of compo- nents, for example, by adding a stimulatory ligand, and second, to change a system component while keeping the context constant. The latter experiment can be useful to test redundancy and specificity among related proteins. If one component is swapped for another within the same context and a different outcome is observed, there must be intrinsic differences in the components. To determine how individual MAP3Ks confer specificity in their responses in vivo, we have focused on two members of the tyrosine kinase-like (TKL) group (Manning et al. 2002) in the Drosophila model sys- tem, mixed lineage kinase (MLK) encoded by the slpr gene and transforming growth factor-b activated kinase (Tak1).

Among the MAP3Ks that stimulate JNK activation, the mixed lineage kinase group consisting of the MLKs, the dual leucine zipper kinases (DLKs), and zipper sterile alpha kinase (ZAK), is the largest, related by sequence homology within the kinase domain and the presence of leucine zipper (LZ) dimerization motifs (Gallo and Johnson 2002). …

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